顔写真

コダマ エイイチ
児玉 栄一
Eiichi Kodama
所属
災害科学国際研究所 災害医学研究部門 災害感染症学分野
職名
教授
学位
  • 博士(医学)(福島県立医科大学)

経歴 12

  • 2020年8月 ~ 継続中
    東北大学大学院 医学系研究科 兼務教授

  • 2020年8月 ~ 継続中
    東北大学病院 兼務教授

  • 2020年8月 ~ 継続中
    東北メディカル・メガバンク機構

  • 2016年6月 ~ 継続中
    東北大学 災害化学国際研究所 災害感染症学分野 教授

  • 2013年4月 ~ 2016年3月
    東北大学 医学系研究科 宮城地域医療支援寄附講座 講師

  • 2013年1月 ~ 2013年3月
    東北大学 東北メディカルメガバンク機構 講師

  • 2009年4月 ~ 2012年12月
    東北大学病院 内科 総合感染症科 助教

  • 1999年9月 ~ 2009年3月
    京都大学 ウイルス研究所 助教

  • 1998年4月 ~ 1999年8月
    福島県立医科大学 微生物学講座 講師

  • 1996年5月 ~ 1998年3月
    NIH/NCL レトロウイルス部門

  • 1995年10月 ~ 1996年4月
    アラバマ州立大学 小児科学講座

  • 1994年4月 ~ 1995年9月
    福島県立医科大学 細菌学講座 助手

︎全件表示 ︎最初の5件までを表示

学歴 2

  • 福島県立医科大学 医学系研究科

    1990年4月 ~ 1994年3月

  • 福島県立医科大学 医学部

    ~ 1990年3月31日

所属学協会 9

  • 国際抗ウイルス学会

  • 抗ウイルス療法学会

  • 日本ケミカルバイオロジー学会

  • 日本エイズ学会

  • 日本バイオセーフティ学会

  • 日本災害医学会

  • 日本環境感染学会

  • 日本感染症学会

  • 日本ウイルス学会

︎全件表示 ︎最初の5件までを表示

研究キーワード 5

  • 感染制御

  • 抗菌剤

  • 薬剤耐性

  • 抗ガン剤

  • 抗ウイルス剤

研究分野 4

  • ライフサイエンス / 薬系化学、創薬科学 /

  • ライフサイエンス / 医療管理学、医療系社会学 /

  • ライフサイエンス / 感染症内科学 /

  • ライフサイエンス / ウイルス学 /

論文 166

  1. Progress report of the Tohoku Medical Megabank Community-Based Cohort Study: Study profile of the repeated center-based survey during second period in Miyagi Prefecture.

    Atsushi Hozawa, Kumi Nakaya, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Junichi Sugawara, Eiichi Kodama, Yohei Hamanaka, Tomoko Kobayashi, Akira Uruno, Naho Tsuchiya, Takumi Hirata, Akira Narita, Akito Tsuboi, Toru Tamahara, Akihito Otsuki, Maki Goto, Makiko Taira, Ritsuko Shimizu, Kichiya Suzuki, Taku Obara, Masahiro Kikuya, Hirohito Metoki, Mami Ishikuro, Inaho Danjoh, Soichi Ogishima, Satoshi Nagaie, Naoko Minegishi, Masahiro Hiratsuka, Kazuki Kumada, Ichiko Nishijima, Takahiro Nobukuni, Yumi Yamaguchi-Kabata, Fuji Nagami, Shigeo Kure, Nobuo Fuse, Kengo Kinoshita, Yoko Izumi, Shinichi Kuriyama, Masayuki Yamamoto

    Journal of epidemiology 2024年2月24日

    DOI: 10.2188/jea.JE20230241  

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    BACKGROUND: The purpose of this study was to report the basic profile of the Miyagi Prefecture part of a repeated center-based survey during the second period (2nd period survey) of the Tohoku Medical Megabank Community-Based Cohort Study (TMM CommCohort Study), as well as the participants' characteristics based on their participation type in the baseline survey. METHODS: The 2nd period survey, conducted from June 2017 to March 2021, included participants of the TMM CommCohort Study (May 2013 to March 2016). In addition to the questionnaire, blood, urine, and physiological function tests were performed during the 2nd period survey. There were three main ways of participation in the baseline survey: Type 1, Type 1 additional, or Type 2 survey. The 2nd period survey was conducted in the same manner as the Type 2 survey, which was based on the community support center (CSC). RESULTS: In Miyagi Prefecture, 29,383 (57.7%) of 50,967 participants participated in the 2nd period survey. The participation rate among individuals who had visited the CSC was approximately 80%. Although some factors differed depending on the participation type in the baseline survey, the 2nd period survey respondents in the Type 1 and Type 2 survey groups at baseline had similar traits. CONCLUSIONS: The 2nd period survey of the TMM CommCohort Study provided detailed follow-up information. Following up on the health conditions of the participants will clarify the long-term effects of disasters and contribute to personalized prevention.

  2. Helical peptides with disordered regions for measles viruses provide new generalized insights into fusion inhibitors. 国際誌

    Kazushige Hirata, Aoi Takahara, Satoshi Suzuki, Shumei Murakami, Kumi Kawaji, Akie Nishiyama, Mina Sasano, Mariko Shoji-Ueno, Emiko Usui, Kazutaka Murayama, Hironori Hayashi, Shinya Oishi, Eiichi N Kodama

    iScience 27 (2) 108961-108961 2024年2月16日

    DOI: 10.1016/j.isci.2024.108961  

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    Despite effective vaccines, measles virus (MeV) outbreaks occur sporadically. Therefore, developing anti-MeV agents remains important for suppressing MeV infections. We previously designed peptide-based MeV fusion inhibitors, M1 and M2, that target MeV class I fusion protein (F protein). Here, we developed a novel fusion inhibitor, MEK35, that exerts potent activity against M1/M2-resistant MeV variants. Comparing MEK35 to M1 derivatives revealed that combining disordered and helical elements was essential for overcoming M1/M2 resistance. Moreover, we propose a three-step antiviral process for peptide-based fusion inhibitors: (i) disordered peptides interact with F protein; (ii) the peptides adopt a partial helical conformation and bind to F protein through hydrophobic interactions; and (iii) subsequent interactions involving the disordered region of the peptides afford a peptide-F protein with a high-affinity peptide-F protein interaction. An M1-resistant substitution blocks the second step. These results should aid the development of novel viral fusion inhibitors targeting class I F protein.

  3. Improving diagnostic accuracy of blood culture-positive cases in a cancer center via an antimicrobial stewardship program and infectious disease consultations. 国際誌

    Naoya Itoh, Nana Akazawa, Takanori Kawabata, Makoto Yamaguchi, Eiichi N Kodama, Norio Ohmagari

    Scientific reports 14 (1) 2869-2869 2024年2月4日

    DOI: 10.1038/s41598-024-53543-w  

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    The direct impact of antimicrobial stewardship programs (ASP) and infectious disease (ID) consultations on patients' clinical diagnoses remains unknown. We assessed their influence on improving the diagnostic accuracy of blood culture-positive inpatients at a Japanese cancer center. Our single-center, retrospective observational study was conducted from April 1, 2018 to March 31, 2022 to evaluate two phases: pre-intervention (notification of antimicrobials by the infection control team) and post-intervention (ASP implementation and ID consultation service establishment). There were 42,514 inpatients: 22,096 during the pre-intervention and 20,418 during the intervention periods. A total of 939 blood culture-positive episodes (pre-intervention, n = 434; post-intervention, n = 505) were analyzed. During the pre-intervention period, 28.1% of the patients had an unknown diagnosis, which decreased significantly to 1.2% post-intervention. Furthermore, hepatobiliary tract and other infections increased significantly post-intervention, and the mortality rate due to Staphylococcus aureus infection decreased from 28.6% pre-intervention to 10.4% post-intervention. The trend and level of the total number of culture specimens submitted per 1000 patient days for all culture specimens increased significantly post-intervention. Notably, the two-set rate of monthly blood cultures increased significantly. In conclusion, improving the overall diagnostic process with ASP and ID consultations at cancer centers could lead to the optimization of patient care.

  4. Real-world effectiveness of full and booster mRNA vaccination for coronavirus disease 2019 against disease severity during the delta- and omicron-dominant phases: A propensity score-matched cohort study using the nationwide registry data in Japan. 国際誌

    Tetsuya Suzuki, Yusuke Asai, Shinya Tsuzuki, Hidetoshi Nomoto, Nobuaki Matsunaga, Eiichi N Kodama, Kayoko Hayakawa, Norio Ohmagari

    Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi 2023年12月10日

    DOI: 10.1016/j.jmii.2023.12.002  

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    BACKGROUND: To date, few studies from the Asian region have reported the effectiveness of messenger ribonucleic acid coronavirus disease 2019 (COVID-19) vaccines against disease progression and death after hospitalization. METHODS: We evaluated the data from the COVID-19 registry in Japan during the delta- and omicron-dominant phases. A propensity score-matched cohort study was conducted between the incompletely (0-1 dose) and fully (2 doses) vaccinated groups during the delta-dominant phase and among the incompletely, fully, and booster (3 doses) vaccinated groups during the omicron-dominant phase. RESULTS: In the delta-dominant phase, 411 pairs were matched. The fully vaccinated group showed a significantly lower oxygen supplementation rate (24.1 % vs. 41.1 %, p < 0.001) but little difference in the mortality rate (2.2 % vs. 2.9 %, p = 0.66). In the omicron-dominant phase, 1494 pairs from the incompletely and fully vaccinated groups, and 425 pairs from the fully and booster vaccinated groups were matched. Full vaccination reduced both the oxygen supplementation rate (18.6 % vs 25.7 %, p < 0.001) and mortality rate (0.7 % vs 2.3 %, p < 0.001). Booster vaccination showed little difference in either the rate of oxygen supplementation (21.2 % vs. 24.7 %, p = 0.25) or mortality (1.2 % vs. 2.6 %, p = 0.21) compared with full vaccination. CONCLUSIONS: Full vaccination reduced disease severity during the delta- and omicron-dominant phases; booster vaccination did not further enhance the protective effects against disease progression during the omicron-dominant phase compared to full vaccination. Future vaccine strategies and policy decisions should consider preventing infection or disease progression in the target population, as well as the characteristics of the dominant variant in that phase.

  5. The association between depressive symptoms and masked hypertension in participants with normotension measured at research center. 国際誌

    Sayuri Tokioka, Naoki Nakaya, Kumi Nakaya, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Hirohito Metoki, Takahisa Murakami, Michihiro Satoh, Tomohiro Nakamura, Mami Ishikuro, Taku Obara, Yohei Hamanaka, Masatsugu Orui, Tomoko Kobayashi, Akira Uruno, Eiichi N Kodama, Satoshi Nagaie, Soichi Ogishima, Yoko Izumi, Nobuo Fuse, Shinichi Kuriyama, Atsushi Hozawa

    Hypertension research : official journal of the Japanese Society of Hypertension 2023年10月31日

    DOI: 10.1038/s41440-023-01484-8  

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    Masked hypertension is a risk factor for cardiovascular diseases. However, masked hypertension is sometimes overlooked owing to the requirement for home blood pressure measurements for diagnosing. Mental status influences blood pressure. To reduce undiagnosed masked hypertension, this study assessed the association between depressive symptoms and masked hypertension. This cross-sectional study used data from the Tohoku Medical Megabank Project Community-Based Cohort Study (conducted in Miyagi Prefecture, Japan, from 2013) and included participants with normotension measured at the research center (systolic blood pressure<140 mmHg and diastolic blood pressure <90 mmHg). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (Japanese version). Masked hypertension was defined as normotension measured at the research center and home hypertension (home systolic blood pressure ≥135 mmHg or home diastolic blood pressure ≥85 mmHg). The study comprised 6705 participants (mean age: 55.7 ± 13.7 years). Of these participants, 1106 (22.1%) without depressive symptoms and 393 (23.2%) with depressive symptoms were categorized to have masked hypertension. Sex-specific and age-adjusted least mean squares for home blood pressure, not for research blood pressure were significantly higher in the group with depressive symptoms in both sex categories. The multivariate odds ratio for masked hypertension in the patients with depressive symptoms was 1.72 (95% confidence interval: 1.26-2.34) in male participants and 1.30 (95% confidence interval: 1.06-1.59) in female ones. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at the research center. Depressive symptoms may be one of the risk factors for masked hypertension. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at research center.

  6. The risk of withdrawal from hypertension treatment in coastal areas after the Great East Japan Earthquake: the TMM CommCohort Study. 国際誌

    Rieko Hatanaka, Naoki Nakaya, Mana Kogure, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Hideaki Hashimoto, Tomohiro Nakamura, Kotaro Nochioka, Taku Obara, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Akira Uruno, Eiichi N Kodama, Nobuo Fuse, Shinichi Kuriyama, Atsushi Hozawa

    Hypertension research : official journal of the Japanese Society of Hypertension 2023年10月13日

    出版者・発行元:Springer Science and Business Media LLC

    DOI: 10.1038/s41440-023-01454-0  

    ISSN:0916-9636

    eISSN:1348-4214

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    Abstract This study aimed to examine whether risk of withdrawal from HTTx was higher in coastal areas that were severely damaged by tsunami than in inland areas. We conducted a cross-sectional study of 9218 participants aged ≥20 years in Miyagi, Japan. The odds ratios (ORs) and confidence interval (CI) for withdrawal from HTTx in coastal and inland groups were compared using multivariate logistic regression analysis, adjusting for potential confounders. In total, 194 of 5860 and 146 of 3358 participants in the inland and coastal groups, respectively, withdrew from HTTx treatment. OR (95%CI) of withdrawal from HTTx in the coastal group was 1.46 (1.14–1.86) compared to the inland group. According to housing damage, ORs (95% CI) in the no damage, partially destroyed, and more than half destroyed coastal groups compared with the no damage inland group were 1.62 (1.04–2.50), 1.69 (1.17–2.45), and 1.08 (0.71–1.65), respectively. In conclusion, the risk of HTTx withdrawal for participants whose homes in coastal areas were relatively less damaged was significantly higher compared with those in inland areas, while the risk of HTTx withdrawal for participants whose homes were more than half destroyed was not. Post-disaster administrative support for disaster victims is considered vital for continuation of their treatment.

  7. Influence of Diabetes Family History on the Associations of Combined Genetic and Lifestyle Risks with Diabetes in the Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Ichiro Tsuji, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Journal of atherosclerosis and thrombosis 2023年10月6日

    DOI: 10.5551/jat.64425  

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    AIM: The influence of family history of diabetes, probably reflecting genetic and lifestyle factors, on the association of combined genetic and lifestyle risks with diabetes is unknown. We examined these associations. METHODS: This cross-sectional study included 9,681 participants in the Tohoku Medical Megabank Community-based Cohort Study. A lifestyle score, which was categorized into ideal, intermediate, and poor lifestyles, was given. Family history was obtained through a self-reported questionnaire. A polygenic risk score (PRS) was constructed in the target data (n=1,936) using publicly available genome-wide association study summary statistics from BioBank Japan. For test data (n=7,745), we evaluated PRS performance and examined the associations of combined family history and genetic and lifestyle risks with diabetes. Diabetes was defined as non-fasting blood glucose ≥ 200 mmHg, HbA1c ≥ 6.5%, and/or self-reported diabetes treatment. RESULTS: In test data, 467 (6.0%) participants had diabetes. Compared with a low genetic risk and an ideal lifestyle without a family history, the odds ratio (OR) was 3.73 (95% confidence interval [CI], 1.92-7.00) for a lower genetic risk and a poor lifestyle without a family history. Family history was significantly associated with diabetes (OR, 3.58 [95% CI, 1.73-6.98]), even in those with a low genetic risk and an ideal lifestyle. Even among participants who had an ideal lifestyle without a family history, a high genetic risk was associated with diabetes (OR, 2.49 [95% CI, 1.65-3.85]). Adding PRS to family history and conventional lifestyle risk factors improved the prediction ability for diabetes. CONCLUSIONS: Our findings support the notion that a healthy lifestyle is important to prevent diabetes regardless of genetic risk.

  8. Association of Central Blood Pressure and Carotid Intima Media Thickness with New-Onset Hypertension in People with High Normal Blood Pressure.

    Sayuri Tokioka, Naoki Nakaya, Kumi Nakaya, Masato Takase, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Hirohito Metoki, Takahisa Murakami, Michihiro Satoh, Tomohiro Nakamura, Taku Obara, Yohei Hamanaka, Tomoko Kobayashi, Akira Uruno, Junichi Sugawara, Eiichi N Kodama, Soichi Ogishima, Yoko Izumi, Nobuo Fuse, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of atherosclerosis and thrombosis 2023年7月5日

    DOI: 10.5551/jat.64151  

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    AIM: People with high normal blood pressure (BP) have a higher risk of cardiovascular events than those with normal BP; therefore, progression to hypertension (HT) should be prevented. We aimed to assess the HT risk using central BP and carotid intima media thickness (CIMT) in people with high normal BP. METHODS: This prospective cohort study used the Tohoku Medical Megabank Community-Based Project Cohort Study (conducted from 2013 in Miyagi Prefecture in Japan). The participants had a high normal BP, defined as a systolic BP of 120-139 mmHg and diastolic BP <90 mmHg using brachial BP measurement during the baseline survey. The outcome was new-onset HT during the secondary survey, conducted four years after the baseline survey. RESULTS: Overall, 4,021 participants with high normal BP during the baseline survey, with an average age of 58.7 years, were included; 1,030 (26%) were diagnosed with new-onset HT during the secondary survey, 3.5± 0.7 years after the baseline survey. The multivariable odds ratio (95% confidence interval) for HT in the highest versus lowest quartile of central BP was 1.7 (1.2-2.4, p=0.0030), and that of CIMT was 1.8 (1.4-2.4, p<0.001). Subgroup analysis according to age (<60 and ≥ 60 years) and sex revealed that the central BP was influential in groups with younger age and female individuals; CIMT was influential in all groups. CONCLUSIONS: Higher central BP and thicker CIMT at the baseline were correlated with new-onset HT in individuals with high normal BP, independent of brachial systolic BP and other cardiovascular risk factors.

  9. Rapid Detection of SARS-CoV-2 RNA Using Reverse Transcription Recombinase Polymerase Amplification (RT-RPA) with Lateral Flow for N-Protein Gene and Variant-Specific Deletion-Insertion Mutation in S-Protein Gene. 国際誌

    Jose L Malaga, Monica J Pajuelo, Michiko Okamoto, Emmanuel Kagning Tsinda, Kanako Otani, Pablo Tsukayama, Lucero Mascaro, Diego Cuicapuza, Masamichi Katsumi, Kazuhisa Kawamura, Hidekazu Nishimura, Akie Sakagami, Yo Ueki, Suguru Omiya, Satoshi Okamoto, Asami Nakayama, Shin-Ichi Fujimaki, Chuyao Yu, Sikandar Azam, Eiichi Kodama, Clyde Dapat, Hitoshi Oshitani, Mayuko Saito

    Viruses 15 (6) 2023年5月26日

    DOI: 10.3390/v15061254  

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    Rapid molecular testing for severe acute respiratory coronavirus 2 (SARS-CoV-2) variants may contribute to the development of public health measures, particularly in resource-limited areas. Reverse transcription recombinase polymerase amplification using a lateral flow assay (RT-RPA-LF) allows rapid RNA detection without thermal cyclers. In this study, we developed two assays to detect SARS-CoV-2 nucleocapsid (N) gene and Omicron BA.1 spike (S) gene-specific deletion-insertion mutations (del211/ins214). Both tests had a detection limit of 10 copies/µL in vitro and the detection time was approximately 35 min from incubation to detection. The sensitivities of SARS-CoV-2 (N) RT-RPA-LF by viral load categories were 100% for clinical samples with high (>9015.7 copies/µL, cycle quantification (Cq): < 25) and moderate (385.5-9015.7 copies/µL, Cq: 25-29.9) viral load, 83.3% for low (16.5-385.5 copies/µL, Cq: 30-34.9), and 14.3% for very low (<16.5 copies/µL, Cq: 35-40). The sensitivities of the Omicron BA.1 (S) RT-RPA-LF were 94.9%, 78%, 23.8%, and 0%, respectively, and the specificity against non-BA.1 SARS-CoV-2-positive samples was 96%. The assays seemed more sensitive than rapid antigen detection in moderate viral load samples. Although implementation in resource-limited settings requires additional improvements, deletion-insertion mutations were successfully detected by the RT-RPA-LF technique.

  10. Mental Health Problems among University Students under the Prolonged COVID-19 Pandemic in Japan: A Repeated Cross-Sectional Survey.

    Moe Seto, Hitomi Usukura, Yasuto Kunii, Yumiko Hamaie, Eiichi N Kodama, Yuko Makino, Yoshitaka Kinouchi, Chihiro Ito, Tadayoshi Ikeda, Hiroaki Tomita

    The Tohoku journal of experimental medicine 260 (1) 1-11 2023年5月1日

    DOI: 10.1620/tjem.2023.J012  

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    Numerous studies have investigated the impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health among university students within a year of its onset, but few have examined the impact of a prolonged pandemic on university life. This study aimed to evaluate the impact of the COVID-19 pandemic on the mental health of students in a large university community. Online questionnaire surveys were conducted on students from March 24 to April 14 (first survey, n = 3,357) and December 2-23, 2021 (second survey, n = 2,604). The questionnaires included items on demographic data, living conditions, and mental health status as measured using the Patient Health Questionnaire-9 for depressive symptoms and the Generalized Anxiety Disorder-7 scale for anxiety symptoms. The results showed that, compared with undergraduate students, graduate students, except those in Medicine, Dentistry, and Pharmaceutical Science courses, had more anxiety symptoms. Furthermore, among undergraduate students, depressive and anxiety symptoms were significantly higher in fourth- than in first-year students. Logistic regression analyses of data from both surveys revealed the seven risk factors associated with depressive or anxiety symptoms that affected the mental health of university students throughout the COVID-19 pandemic: 1) female or nonbinary gender, 2) graduate student, 3) quarantine experience due to COVID-19, 4) isolation from friends and acquaintances, 5) disorganized pattern of daily life, 6) worse financial situation, and 7) no availability of consultations regarding health, life, and finances. These findings suggest that mental health measures for university students need to be designed specific to each course.

  11. Combined fat mass and fat-free mass indices and lung function among Japanese population: The Tohoku Medical Megabank Community-based Cohort Study.

    Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of epidemiology 2023年4月8日

    DOI: 10.2188/jea.JE20220355  

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    BACKGROUND: Although fat mass index (FMI) and fat-free mass index (FFMI) affect lung function, FMI and FFMI are not independent of each other since FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. We aimed to examine the association of combined FMI and FFMI with lung function. METHODS: In this cross-sectional study, lung function was evaluated using forced expiratory volume at 1 s and forced vital capacity was measured using spirometry. Both FMI and FFMI were classified into sex-specific quartiles (16 groups). Analysis of covariance was used to assess the associations of combined FMI and FFMI with lung function. The trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1-4 (lowest-highest), and entering the number as a continuous term in the regression model. RESULTS: This study included 3,736 men and 8,821 women aged ≥20 years living in Miyagi Prefecture, Japan. The mean FEV1 (standard deviation) was 3.0 (0.7) L for men and 2.3 (0.5) L for women. The mean FVC was 3.8 (0.7) L for men and 2.8 (0.5) L for women. The FMI was inversely associated with lung function among all FFMI subgroups in both sexes. Conversely, FFMI was positively associated with lung function in all FMI subgroups in both sexes. CONCLUSIONS: Higher FMI was associated with lower lung function independent of FFMI; higher FFMI was associated with higher lung function independent of FMI. Reducing FMI and maintaining FFMI might be important for respiratory health.

  12. Association between lung function and hypertension and home hypertension in a Japanese population: the Tohoku Medical Megabank Community-Based Cohort Study. 国際誌

    Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of hypertension 41 (3) 443-452 2023年3月1日

    DOI: 10.1097/HJH.0000000000003356  

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    BACKGROUND: Although several studies have shown an inverse association between lung function and hypertension, few studies have examined the association between lung function and hypertension among never-smokers, and no study has investigated the association between lung function and home hypertension. We investigated the associations between lung function and hypertension in a Japanese population. INDIVIDUALS AND METHODS: We conducted a cross-sectional study of 3728 men and 8795 women aged 20 years or older living in Miyagi Prefecture, Japan. Lung function was assessed using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC), measured by spirometry. Hypertension was defined as a casual blood pressure at least 140/90 mmHg and/or self-reported treatment for hypertension. Home hypertension was defined as morning home blood pressure at least 135/85 mmHg and/or self-reported treatment for hypertension. Multivariate logistic regression models adjusted for potential confounders were used to assess the association between lung function and hypertension. RESULTS: The mean ages (±SD) of men and women were 60.1 (±14.0) years and 56.2 (±13.4) years, respectively, and 1994 (53.5%) men and 2992 (34.0%) women had hypertension. In the multivariable models, FEV1 and FVC were inversely associated with hypertension. Inverse associations between lung function and hypertension were observed even among never-smokers. Furthermore, reduced lung function was associated with higher prevalence of home hypertension in men and women. CONCLUSION: Reduced lung function was associated with higher prevalence of hypertension, independent of smoking status. Assessment of the lung function or blood pressure may be required in individuals with reduced lung function or hypertension.

  13. Nasopharyngeal SARS-CoV-2 may not be dispersed by a high-flow nasal cannula. 国際誌

    Tetsuya Suzuki, Shinichiro Morioka, Kei Yamamoto, Sho Saito, Shun Iida, Katsuji Teruya, Jin Takasaki, Masayuki Hojo, Kayoko Hayakawa, Satoshi Kutsuna, Sho Miyamoto, Seiya Ozono, Tadaki Suzuki, Eiichi N Kodama, Norio Ohmagari

    Scientific reports 13 (1) 2669-2669 2023年2月15日

    DOI: 10.1038/s41598-023-29740-4  

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    A high-flow nasal cannula (HFNC) therapy plays a significant role in providing respiratory support to critically ill patients with coronavirus disease 2019 (COVID-19); however, the dispersion of the virus owing to aerosol generation is a matter of concern. This study aimed to evaluate if HFNC disperses the virus into the air. Among patients with COVID-19 admitted to private rooms with controlled negative pressure, we enrolled those admitted within 10 days of onset and requiring oxygenation through a conventional nasal cannula or HFNC therapy. Of the 17 patients enrolled, we obtained 22 samples (11 in the conventional nasal cannula group and 11 in the HFNC group). Viral RNA was detected in 20 nasopharyngeal swabs, and viable viruses were isolated from three nasopharyngeal swabs. Neither viral RNA nor viable virus was detected in the air sample at 0.5 m regardless of the oxygen-supplementation device. We detected viral RNA in two samples in the conventional nasal cannula group but not in the HFNC therapy group in gelatin filters located 3 m from the patient and the surface of the ventilation. This study directly demonstrated that despite viral RNA detection in the nasopharynx, viruses may not be dispersed by HFNC therapy. This warrants further research to determine if similar results can be obtained under different conditions.

  14. Carotid Intima Media Thickness and Risk Factor for Atherosclerosis: Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of atherosclerosis and thrombosis 2023年2月11日

    DOI: 10.5551/jat.64039  

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    AIM: We examined the association between the carotid intima medica thickness (cIMT) and risk factors for atherosclerosis based on the Japan Atherosclerosis Society 2022 Atherosclerosis Prevention Guideline. METHODS: Using data from the Tohoku Medical Megabank Community-based Cohort Study, we performed a cross-sectional study that enrolled 13,366 participants (age ≥ 20 years) with an analysis of covariance to assess associations between cIMT and risk factors for atherosclerosis. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. Analysis was conducted in the model adjusted for age, sex, smoking status, drinking status, body mass index (BMI), systolic blood pressure (SBP), glycated hemoglobin (HbA1c), high-density lipoprotein-cholesterol (HDL-C), non-high-density lipoprotein-cholesterol (non-HDL-C), and height. RESULTS: In this study cohort, the average age and cIMT were 57.3 (13.8) years and 0.61 (0.13) mm, respectively, which included 3,988 males (29.8%). Males had a higher cIMT than did the females. Age, height, BMI, SBP, HbA1c, and non-HDL-C were positively associated with cIMT. HDL-C was inversely associated with cIMT. Compared with never drinkers, current drinkers (≥ 46.0 g/day) had a significantly decreased cIMT. CONCLUSIONS: The cIMT was associated with atherosclerosis risk factors including age, sex, BMI, SBP, HbA1c, non-HDL-C, and HDL-C, and adequate control of risks in high-risk individuals might be required to prevent atherosclerotic cardiovascular diseases.

  15. 大規模震災における精神科病棟の災害時の実態と災害時感染症対策に関する研究報告

    吉村, 直仁, 伊勢野, 明美, 高原, 円, 児玉, 栄一, 杉森, 裕樹, 野崎, 裕之

    医療創生大学研究紀要 = The Research Bulletin of Iryo Sosei University 3 (36) 37-45 2023年2月

    ISSN:2436-1437

  16. Design and Progress of Child Health Assessments at Community Support Centers in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank Project.

    Tomoko Kobayashi, Mika Kobayashi, Naoko Minegishi, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Tomomi Onuma, Keiko Murakami, Fumihiko Ueno, Aoi Noda, Akira Uruno, Junichi Sugawara, Kichiya Suzuki, Eiichi N Kodama, Yohei Hamanaka, Naho Tsuchiya, Mana Kogure, Naoki Nakaya, Makiko Taira, Mika Sakurai-Yageta, Toru Tamahara, Junko Kawashima, Maki Goto, Akihito Otsuki, Ritsuko Shimizu, Soichi Ogishima, Hiroaki Hashizume, Fuji Nagami, Tomohiro Nakamura, Atsushi Hozawa, Tadao Kobayashi, Nobuo Fuse, Shinichi Kuriyama, Shigeo Kure, Masayuki Yamamoto

    The Tohoku journal of experimental medicine 259 (2) 93-105 2023年1月20日

    DOI: 10.1620/tjem.2022.J103  

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    The Tohoku Medical Megabank Project (TMM) has been conducting a birth and three-generation cohort study (the BirThree Cohort Study). We recruited 73,529 pregnant women and their family members for this cohort study, which included 23,143 newborns and 9,459 of their siblings. We designed and are in the process of conducting three-step health assessments for each newborn at approximately ages of 5, 10 and 16. These health assessments are administered at seven community support centers. Trained genome medical research coordinators conduct physical examinations of and collect biological specimens from each participant. The Sendai Children's Health Square has been established as the headquarters for these child health assessments and is utilized to accumulate knowledge that can facilitate the proper practice of child health assessments. We designed all the relevant health assessments facilities to allow parents and their children to participate in the health assessments concomitantly. Our centers serve as places where child participants and their parents can feel at ease as a result of the implementation of safety measures and child hospitality measures. The TMM BirThree Cohort Study is in the process of conducting strategically detailed health assessments and genome analysis, which can facilitate studies concerning the gene-environment interactions relevant to noncommunicable diseases. Through these operations, our study allows for a significant depth of data to be collected in terms of the number of biospecimens under study and the comprehensiveness of both basic and clinical data alongside relevant family information.

  17. Helix-based screening with structure prediction using artificial intelligence has potential for the rapid development of peptide inhibitors targeting class I viral fusion

    Satoshi Suzuki, Mio Kuroda, Keisuke Aoki, Kumi Kawaji, Yoshiki Hiramatsu, Mina Sasano, Akie Nishiyama, Kazutaka Murayama, Eiichi N. Kodama, Shinya Oishi, Hironori Hayashi

    RSC Chemical Biology 2023年

    出版者・発行元:Royal Society of Chemistry (RSC)

    DOI: 10.1039/d3cb00166k  

    eISSN:2633-0679

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    Peptide inhibitors against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are designed using a screening system for peptide-based inhibitors containing an α-helix region (SPICA) and structures predicted by AlphaFold2.

  18. Investigation of oral macrolide prescriptions in Japan using a retrospective claims database, 2013-2018. 国際誌

    Satoshi Ide, Masahiro Ishikane, Kensuke Aoyagi, Akane Ono, Yusuke Asai, Shinya Tsuzuki, Yoshiki Kusama, Yoshiaki Gu, Eiichi Kodama, Norio Ohmagari

    PloS one 18 (6) e0287297 2023年

    DOI: 10.1371/journal.pone.0287297  

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    Macrolide usage in Japan exceeds that in Europe and the United States. Investigating the actual conditions in which macrolides are used is important for identifying further interventions for appropriate antimicrobial use; however, this situation has not been evaluated in Japan. Therefore, we aimed to clarify the number of macrolide prescriptions and their changes before and after implementation of the Antimicrobial Resistance (AMR) Action Plan. In addition, we also investigated the names of diseases for which macrolides have been prescribed and the number of days of prescription. A retrospective observational study was conducted using JMDC claims data from January 2013 to December 2018. The proportion of all oral antimicrobials and macrolides used during this period and the diseases for which macrolides were used in the 3 years before and after the AMR Action Plan were determined separately for acute (< 14 prescription days) and chronic (> 14 prescription days) diseases. The number of prescriptions for macrolides constituted approximately 30% of those for all oral antimicrobials; of these, clarithromycin accounted for approximately 60%. Most prescriptions for acute diseases were for common cold, whereas allergic and dermatological diseases were included among chronic diseases. The names of these illnesses did not change before and after the AMR Action Plan. Overall, these results indicate that appropriate macrolide use involves a review of their use for common cold along with appropriate evaluation of their long-term use for skin and allergic diseases. They also indicate the need for further fact-finding studies and ongoing AMR measures.

  19. Reduction strategies for inpatient oral third-generation cephalosporins at a cancer center: An interrupted time-series analysis. 国際誌

    Naoya Itoh, Takanori Kawabata, Nana Akazawa, Daichi Kawamura, Hiromi Murakami, Yuichi Ishibana, Eiichi N Kodama, Norio Ohmagari

    PloS one 18 (2) e0281518 2023年

    DOI: 10.1371/journal.pone.0281518  

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    Oral third-generation cephalosporins (3GCs) are not recommended for use owing to their low bioavailability and the risk of emergence of resistant microorganisms with overuse. A standardized and effective method for reducing their use is lacking. Here, in a 60-month, single-institution, interrupted time-series analysis, which was retrospectively conducted between April 1, 2017, and March 31, 2022, we evaluated the effectiveness of a four-phase intervention to reduce the use of 3GCs in patients at a cancer center: Phase 1 (pre-intervention), Phase 2 (review of clinical pathways), Phase 3 (establishment of infectious disease consultation service and implementation of antimicrobial stewardship program), and Phase 4 (educational lecture and pop-up displays for oral antimicrobials at the time of ordering). Although no significant changes were observed in Phases 3 and 4, the first intervention resulted in a significant decrease in the trend and level of days of therapy (DOT) for 3GCs. The level for cephalexin DOT and the trend for sulfamethoxazole-trimethoprim DOT increased in Phase 4, and the trend for amoxicillin and amoxicillin-clavulanate DOT increased in Phase 3. Macrolide DOT showed a decreasing trend in Phases 2 and 4 and decreasing and increased levels in Phases 3 and 4, respectively; no change was observed for quinolones. Actual and adjusted purchase costs of 3GCs decreased significantly during all study periods, while those for oral antimicrobials decreased in Phase 2, and actual purchase costs increased in Phases 3 and 4. No significant reduction in resistant organisms, length of hospital stay, or mortality was observed. This is the first study on the effects of oral 3GC reduction strategies in patients with cancer. We conclude that even facilities that substantially use antimicrobials can efficiently reduce the use of 3GCs.

  20. Lessons learned from an outbreak of COVID-19 in the head and neck surgery ward of a Japanese cancer center during the sixth wave by Omicron. 国際誌

    Naoya Itoh, Nana Akazawa, Masahiro Ishikane, Takanori Kawabata, Daichi Kawamura, Tomoyuki Chikusa, Eiichi N Kodama, Norio Ohmagari

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 (12) 1610-1615 2022年12月

    出版者・発行元:Elsevier BV

    DOI: 10.1016/j.jiac.2022.08.010  

    ISSN:1341-321X

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    INTRODUCTION: We describe a coronavirus disease (COVID-19) outbreak in a cancer center's head and neck surgery ward and the interventions to halt ongoing exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among healthcare workers and patients with cancer. METHODS: Case definition included all healthcare workers and all patients associated to the ward from January 27 to January 31, 2022 with a positive SARS-COV-2 antigen test. This retrospective descriptive study was conducted between January 27, 2022, and February 14, 2022. RESULTS: From January 28, 2022, to February 9, 2022, 84 cases (36 healthcare workers, 48 patients) were screened, and 26 (12 healthcare workers, 14 patients) were identified as SARS-CoV-2-positive. The proportion of healthcare providers who performed aerosol generating procedures on positive patients was 91% for positive cases and 49% for non-cases. Room sharing with patients with COVID-19 was 64% for positive cases and 21% for non-cases (57% vs. 21% with positive tracheostomy patients; 43% vs. 9% with positive cases using a nebulizer; 50% vs. 15% with positive cases requiring sputum suctioning, respectively). Compliance with the universal masking policy for patients was 36% of positive cases and 79% of non-cases. CONCLUSIONS: This is the first report of a nosocomial outbreak of COVID-19 in a head and neck surgery ward during the Omicron pandemic. Notably, there were a high number of positive cases among healthcare workers who performed aerosol generating procedures for positive patients and patients who shared the room with a patient with COVID-19 with the potential to generate aerosols.

  21. The Association of Lung Function and Carotid Intima-Media Thickness in a Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of atherosclerosis and thrombosis 2022年11月4日

    DOI: 10.5551/jat.63826  

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    AIM: Impaired lung function is associated with atherosclerotic vascular events. Carotid intima-media thickness (cIMT) is a marker for subclinical atherosclerosis. However, few studies have examined the association between lung function and cIMT among never smokers or individuals stratified by age. We investigated the association between lung function and cIMT in the Japanese population. METHODS: We conducted a cross-sectional study of 3,716 men and 8,765 women aged 20 years or older living in Miyagi Prefecture, Japan. Lung function was evaluated using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC) was measured using spirometry. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between lung function and cIMT and adjusted for potential confounders. A linear trend test was conducted by scoring the categories from 1 (lowest) to 4 (highest) and entering the score as a continuous term in the regression model. RESULTS: After adjusting for potential confounders including passive smoking, lower FEV1 and FVC were associated with higher cIMT in both men and women (P<0.001 for linear trend). This association was confirmed even when we restricted our study to never smokers. Furthermore, even when we stratified by age, an inverse association between lung function and cIMT was confirmed in middle-aged (40-64 years) and elderly participants (65-74 years). CONCLUSIONS: Lower lung function was associated with higher cIMT in the Japanese population independent of age and smoking. Assessment of atherosclerosis or lung function may be required for individuals with lower lung function or atherosclerosis.

  22. Impact of the COVID-19 pandemic on racial and ethnic minorities in Japan. 国際誌

    Hidetoshi Nomoto, Yusuke Asai, Kayoko Hayakawa, Nobuaki Matsunaga, Satoshi Kutsuna, Eiichi N Kodama, Norio Ohmagari

    Epidemiology and infection 1-35 2022年10月26日

    DOI: 10.1017/S0950268822001674  

  23. Comparison of sputum specimens and nasopharyngeal swab specimens for diagnosis of acute human metapneumovirus-related lower respiratory tract infections in adults

    Takehiro Yajima, Hiroshi Takahashi, Nozomu Kimura, Kosuke Sato, Daisuke Jingu, Satoshi Ubukata, Makoto Shoji, Hiroshi Watanabe, Eiichi N. Kodama, Hidekazu Nishimura

    JOURNAL OF CLINICAL VIROLOGY 154 2022年9月

    出版者・発行元:ELSEVIER

    DOI: 10.1016/j.jcv.2022.105238  

    ISSN:1386-6532

    eISSN:1873-5967

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    Background: To detect human metapneumovirus, tests besides reverse transcription-polymerase chain reaction (RT-PCR) on nasopharyngeal swab specimens are less accessible. Immunochromatography assays are rapid and simple without the need of any special equipment but sometimes are insufficiently sensitive. This study describes the usefulness of immunochromatography assays to detect human metapneumovirus in adult patients with human metapneumovirus-related acute lower respiratory tract infection using sputum specimens.Methods: This prospective single-center study enrolled adults and adolescents aged >= 16 years with signs and symptoms of an acute respiratory illness who were diagnosed with acute lower respiratory tract infection. The presence of human metapneumovirus infection was confirmed by semconversion. Immunochromatography assays and real-time RT-PCR were performed to compare the efficacy of nasopharyngeal swab specimens and sputum specimens. Comparative results were obtained via McNemar's test.Results: Overall, 337 patients were recruited in this study; 63 (18.7%) patients were seroconverted. Sputum specimens showed significantly higher positivity rates than nasopharyngeal swab specimens with both immunochromatography assays (p = 0.0008) and real-time RT-PCR = 0.014). Among 29 patients with pneumonia who had concordant positive real-time RT-PCR results for both nasopharyngeal swab specimens and sputum specimens, 21 (72.4%) had a higher viral load in the sputum specimens.Conclusions: Sputum specimens are more useful in detecting human metapneumovirus than nasopharyngeal swab specimens in adult patients with acute lower respiratory tract infection.

  24. Interferon lambda 3 in the early phase of coronavirus disease-19 can predict oxygen requirement. 国際誌

    Tetsuya Suzuki, Noriko Iwamoto, Shinya Tsuzuki, Yuko Kakumoto, Michiyo Suzuki, Shinobu Ashida, Yusuke Oshiro, Takeshi Nemoto, Kohei Kanda, Ayako Okuhama, Gen Yamada, Makoto Inada, Lubna Sato, Yusuke Miyazato, Yutaro Akiyama, Sho Saito, Shinichiro Morioka, Mugen Ujiie, Kayoko Hayakawa, Masaya Sugiyama, Masashi Mizokami, Eiichi N Kodama, Norio Ohmagari

    European journal of clinical investigation 52 (9) e13808 2022年9月

    DOI: 10.1111/eci.13808  

  25. COVID-19 in a Hairy Cell Leukemia Patient: A Rare Case Report.

    Hirohito Sano, Koji Murakami, Hisayuki Yokoyama, Chie Suzuki, Yudai Iwasaki, Eiichi Kodama, Hisatoshi Sugiura

    The Tohoku journal of experimental medicine 258 (1) 63-68 2022年8月10日

    DOI: 10.1620/tjem.2022.J058  

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    The detailed clinical course of coronavirus disease 2019 (COVID-19) in patients with hairy cell leukemia (HCL) is rarely reported. We report the first case of HCL diagnosed with prolonged pancytopenia after COVID-19 infection in Japan. We describe the case of a 56-year-old man who was diagnosed with COVID-19. Computed tomography revealed ground-glass opacities in the bilateral lung lobes as well as splenomegaly. Remdesivir and dexamethasone were administered for the treatment of COVID-19. Since the pancytopenia persisted, bone marrow examination was performed, and he was diagnosed with HCL. Although pancytopenia can occur with COVID-19 alone, clinicians should be alerted regarding the presence of hematologic malignancies in patients in whom pancytopenia persists after COVID-19 treatment or in those with splenomegaly. Further, the condition of all previously reported patients with COVID-19 associated with HCL was severe enough to require mechanical ventilation. This is the first case in which the disease was not severe. The interleukin-6 (IL-6) level was lower in this case than in previous cases, suggesting that racial differences in IL-6 production may have contributed to COVID-19 severity.

  26. Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors. 国際誌

    Yuko Makino, Chihiro Oe, Kazuya Iwama, Satoshi Suzuki, Akie Nishiyama, Kazuya Hasegawa, Haruka Okuda, Kazushige Hirata, Mariko Ueno, Kumi Kawaji, Mina Sasano, Emiko Usui, Toshiaki Hosaka, Yukako Yabuki, Mikako Shirouzu, Makoto Katsumi, Kazutaka Murayama, Hironori Hayashi, Eiichi N Kodama

    Communications biology 5 (1) 619-619 2022年6月23日

    DOI: 10.1038/s42003-022-03555-x  

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    Serine hydroxymethyltransferase (SHMT) produces 5,10-methylenetetrahydrofolate (CH2-THF) from tetrahydrofolate with serine to glycine conversion. SHMT is a potential drug target in parasites, viruses and cancer. (+)-SHIN-1 was developed as a human SHMT inhibitor for cancer therapy. However, the potential of SHMT as an antibacterial target is unknown. Here, we show that (+)-SHIN-1 bacteriostatically inhibits the growth of Enterococcus faecium at a 50% effective concentration of 10-11 M and synergistically enhances the antibacterial activities of several nucleoside analogues. Our results, including crystal structure analysis, indicate that (+)-SHIN-1 binds tightly to E. faecium SHMT (efmSHMT). Two variable loops in SHMT are crucial for inhibitor binding, and serine binding to efmSHMT enhances the affinity of (+)-SHIN-1 by stabilising the loop structure of efmSHMT. The findings highlight the potency of SHMT as an antibacterial target and the possibility of developing SHMT inhibitors for treating bacterial, viral and parasitic infections and cancer.

  27. Associations between the Combined Fat Mass Index and Fat-Free Mass Index with Carotid Intima-Media Thickness in a Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Kichiya Suzuki, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Journal of atherosclerosis and thrombosis 30 (3) 255-273 2022年5月26日

    DOI: 10.5551/jat.63523  

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    AIM: Although many epidemiological studies have shown that obesity assessed by body mass index is associated with carotid intima-media thickness (cIMT), few studies have evaluated fat-free mass, which is a component of body composition. We investigated the associations between the combined fat mass index (FMI) and fat-free mass index (FFMI) with cIMT. METHODS: We conducted a cross-sectional study of 3,873 men and 9,112 women aged 20 years or older who lived in Miyagi prefecture, Japan. The FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. The indices were classified into sex-specific quartiles and were combined into 16 groups. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between the combined FMI and FFMI with cIMT adjusted for age and smoking status. The linear trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1 (lowest) to 4 (highest), and entering the number as a continuous term in the regression model. RESULTS: In multivariable models, a higher FMI was not related to higher cIMT in men and women in most FFMI subgroups. Conversely, a higher FFMI was related to higher cIMT in all FMI subgroups (p<0.001 for linear trend). CONCLUSIONS: FMI was not associated with cIMT in most FFMI subgroups. Conversely, FFMI was positively associated with cIMT independently of FMI.

  28. Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic Site Integrase Inhibitor JTP-0157602. 国際誌

    Yoshitsugu Ohata, Mitsunori Tomonaga, Yasuo Watanabe, Keiko Tomura, Koji Kimura, Tatsuo Akaki, Kaoru Adachi, Eiichi N Kodama, Yuji Matsuzaki, Hironori Hayashi

    Journal of virology 96 (6) e0184321 2022年3月23日

    DOI: 10.1128/JVI.01843-21  

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    HIV-1 integrase (IN) is an essential enzyme for viral replication. Non-catalytic site integrase inhibitors (NCINIs) are allosteric HIV-1 IN inhibitors and a potential new class of antiretrovirals. In this report, we identified a novel NCINI, JTP-0157602, with an original scaffold. JTP-0157602 exhibited potent antiviral activity against HIV-1 and showed a serum-shifted EC90 of 138 nM, which is comparable to the FDA-approved IN strand transfer inhibitors (INSTIs). This compound was fully potent against a wide range of recombinant viruses with IN polymorphisms, including amino acids 124/125, a hot spot of IN polymorphisms. In addition, JTP-0157602 retained potent antiviral activity against a broad panel of recombinant viruses with INSTI-related resistant mutations, including multiple substitutions that emerged in clinical studies of INSTIs. Resistance selection experiments of JTP-0157602 led to the emergence of A128T and T174I mutations, which are located at the lens epithelium-derived growth factor/p75 binding pocket of IN. JTP-0157602 inhibited HIV-1 replication mainly during the late-phase of the replication cycle, and HIV-1 virions produced by reactivation from HIV-1 latently-infected Jurkat cells in the presence of JTP-0157602 were non-infectious. These results suggest that JTP-0157602 and analog compounds can be used to treat HIV-1 infectious diseases. IMPORTANCE Non-catalytic site integrase inhibitors (NCINIs) are allosteric HIV-1 integrase (IN) inhibitors that bind to the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. NCINIs are expected to be a new class of anti-HIV-1 agents. In this study, we present a novel NCINI, JTP-0157602, which has potent activity against a broad range of HIV-1 strains with IN polymorphisms. Furthermore, JTP-0157602 shows strong antiviral activity against IN strand transfer inhibitor-resistant mutations, suggesting JTP-0157602 and its analogs are potential agents to treat HIV-1 infections. Structural modeling indicated that JTP-0157602 binds to the LEDGF/p75 binding pocket of IN, and the results of in vitro resistance induction revealed the JTP-0157602-resistance mechanism of HIV-1. These data shed light on developing novel NCINIs, which exhibit potent activity against HIV-1 with broad IN polymorphisms and multi-drug resistant HIV-1 variants.

  29. Disseminated tuberculosis with paradoxical reactions caused by a Mycobacterium tuberculosis strain belonging to the Indo-Oceanic lineage: An imported case in Japan. 国際誌

    Kengo Oshima, Chie Nakajima, Kazushige Hirata, Hironori Hayashi, Eiichi N Kodama, Yukari Fukushima, Yasuhiko Suzuki, Hajime Kanamori, Hiroaki Baba, Tetsuji Aoyagi, Koichi Tokuda, Mitsuo Kaku

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 (7) 965-970 2022年3月4日

    DOI: 10.1016/j.jiac.2022.02.008  

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    Tuberculosis remains a major public health concern. Millions of tuberculosis cases and associated deaths have been reported worldwide. The Indo-Oceanic lineage Mycobacterium tuberculosis is common in Southeast Asia and causes extrapulmonary lesions. Only a few case studies on this lineage with genetic analysis using whole-genome sequencing have been reported in the literature. We present a case of disseminated tuberculosis, characterized by a variety of extrapulmonary lesions and paradoxical reactions, caused by the Indo-Oceanic lineage M. tuberculosis in a woman in Myanmar. A 22-year-old Burmese woman had arthritis in the right knee, with unknown aetiology, and was referred to our hospital. Computed tomography of the trunk revealed multiple nodular shadows in both lungs; swollen mediastinal lymph nodes; and small, low-density areas in the spleen. M. tuberculosis was detected in the sputum sample, joint aspirate, subcutaneous tumor, and exudate. She experienced a variety of paradoxical reactions together with aggressive tuberculosis dissemination in all areas of the body. Whole-genome sequencing of the DNA of MTB obtained from sputum and the right cervical subcutaneous abscess confirmed the Indo-Oceanic lineage of M. tuberculosis, the predominant strain in Myanmar. The Indo-Oceanic lineage M. tuberculosis causes disseminated tuberculosis all over the body including the periungual region. When patients show unusual symptoms, physicians should consider the introduction of new strains from foreign countries. Genetic analyses of the strains are recommended to define and confirm the lineages.

  30. Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan 国際誌 査読有り

    Nobuo Fuse, Miyuki Sakurai, Ikuko N. Motoike, Kaname Kojima, Takako Takai-Igarashi, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Mami Ishikuro, Taku Obara, Akiko Miyazawa, Kei Homma, Keisuke Ido, Makiko Taira, Tomoko Kobayashi, Ritsuko Shimizu, Akira Uruno, Eiichi N. Kodama, Kichiya Suzuki, Yohei Hamanaka, Hiroaki Tomita, Junichi Sugawara, Yoichi Suzuki, Fuji Nagami, Soichi Ogishima, Fumiki Katsuoka, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Yaegashi, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto

    Ophthalmology Science 2 (1) 100113-100113 2022年3月

    出版者・発行元:Elsevier BV

    DOI: 10.1016/j.xops.2022.100113  

    ISSN:2666-9145

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    PURPOSE: To elucidate the differences in ocular biometric parameters by generation and gender and to identify axial length (AL)-associated genetic variants in Japanese individuals, we analyzed Tohoku Medical Megabank Organization (ToMMo) Eye Study data. DESIGN: We designed the ToMMo Eye Study, examined AL variations, and conducted genome-wide association studies (GWASs). PARTICIPANTS: In total, 33 483 participants aged > 18 years who were recruited into the community-based cohort (CommCohort) and the birth and three-generation cohort (BirThree Cohort) of the ToMMo Eye Study were examined. METHODS: Each participant was screened with an interview, ophthalmic examinations, and a microarray analysis. The GWASs were performed in 22 379 participants in the CommCohort (discovery stage) and 11 104 participants in the BirThree Cohort (replication stage). We evaluated the associations of single nucleotide polymorphisms (SNPs) with AL using a genome-wide significance threshold (5 × 10-8) in each stage of the study and in the subsequent meta-analysis. MAIN OUTCOME MEASURES: We identified the association of SNPs with AL and distributions of AL in right and left eyes and individuals of different sexes and ages. RESULTS: In the discovery stage, the mean AL of the right eye (23.99 mm) was significantly greater than that of the left eye (23.95 mm). This difference was reproducible across sexes and ages. The GWASs revealed 703 and 215 AL-associated SNPs with genome-wide significance in the discovery and validation stages, respectively, and many of the SNPs in the discovery stage were replicated in the validation stage. Validated SNPs and their associated loci were meta-analyzed for statistical significance (P < 5 × 10-8). This study identified 1478 SNPs spread over 31 loci. Of the 31 loci, 5 are known AL loci, 15 are known refractive-error loci, 4 are known corneal-curvature loci, and 7 loci are newly identified loci that are not known to be associated with AL. Of note, some of them shared functional relationships with previously identified loci. CONCLUSIONS: Our large-scale GWASs exploiting ToMMo Eye Study data identified 31 loci linked to variations in AL, 7 of which are newly reported in this article. The results revealed genetic heterogeneity and similarity in SNPs related to ethnic variations in AL.

  31. Change in use of pediatric oral antibiotics in Japan, pre- and post-implementation of an antimicrobial resistance action plan. 国際誌

    Noriko Iwamoto, Naho Morisaki, Kazuhiro Uda, Masashi Kasai, Eiichi N Kodama, Norio Ohmagari, Isao Miyairi

    Pediatrics international : official journal of the Japan Pediatric Society 64 (1) e15197 2022年1月

    DOI: 10.1111/ped.15197  

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    BACKGROUND: Most antimicrobials are prescribed to outpatients, making outpatient antibiotic prescription an important target for antibiotic stewardship. A national antimicrobial resistance (AMR) action plan was developed in 2016 by the Japanese government with various antimicrobials steawardship activities for pediatric outpatients. We aimed to evaluate changes in antibiotic use pre- and post-implementation of the AMR action plan. METHODS: All antimicrobials prescribed to pediatric outpatients in Japan from 2011 to 2018 were retrospectively analyzed using data from a national database. Antimicrobials dispensed for patients aged ≤19 years were reviewed. Antimicrobial use was surveyed by age, year of use, type of antimicrobial prescribed, and prescribing facility. Five cities were selected as pilot areas to investigate the variations, based on the clinical specialties of the prescribing physicians. RESULTS: Antimicrobial usage varied with age. Specifically, usage decreased post-AMR in patients aged ≤8 years and increased in those aged >15 years. Further, antimicrobial prescriptions tended to decrease after 2016 in primary care clinics and hospitals. In the pilot areas of the study, 35% of all oral antimicrobials were prescribed in otolaryngology departments, and 8% were prescribed in dermatology clinics. Notably, antimicrobial prescriptions from both departments showed an upward trend from 2011 to 2018. CONCLUSION: The use of antimicrobial agents decreased in children younger than 8 years in pediatric clinics, hospitals, and internal medicine clinics. However, use increased in children older than 15 years and in other specialty clinics. Settings with an increasing use of antimicrobials are potential targets for the next antibiotic stewardship program and should be investigated in detail.

  32. Factors Associated With Prolonged Psychological Distress Among Nurses and Physicians Engaged in COVID-19 Patient Care in Singapore and Japan. 国際誌

    Shinichiro Morioka, Ban Hock Tan, Hiroe Kikuchi, Yusuke Asai, Tetsuya Suzuki, Shinobu Ashida, Satoshi Kutsuna, Sho Saito, Kayoko Hayakawa, Thuan Tong Tan, Eiichi Kodama, Norio Ohmagari

    Frontiers in psychiatry 13 781796-781796 2022年

    DOI: 10.3389/fpsyt.2022.781796  

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    This study explores the factors contributing to the prolonged psychological distress of frontline nurses and physicians caring for COVID-19 patients in hospitals in Singapore and Japan. A cross-sectional survey between September and December 2020 yielded 1,644 responses (23.8%), from 62 nurses and 64 physicians in Singapore and 1,280 nurses and 238 physicians in Japan. Multivariate logistic regression analysis revealed that significant risk factors for prolonged psychological distress included being a frontline nurse [adjusted odds ratio (aOR) = 2.40, 95% confidence interval (CI): 1.24-4.66], having an underlying medical condition (aOR = 1.74, 95% CI: 1.22-2.46), experiencing prejudice because they undertook COVID-19 patient care (aOR = 3.05, 95% CI: 2.23-4.18), having trouble dealing with panicked or uncooperative patients (aOR = 2.36, 95% CI: 1.71-3.25), and experiencing an outbreak of COVID-19 in the hospital (aOR = 2.05, 95% CI: 1.38-3.04). Factors inversely associated with psychological distress included age (OR = 0.98, 95% CI: 0.97-1.00), number of beds in the hospital (aOR = 0.73, 95% CI: 0.57-0.94), clinical practice of carefully putting on and taking off personal protective equipment in daily COVID-19 patient care (aOR = 0.52, 95% CI: 0.37-0.73), and knowledge on COVID-19 (aOR = 0.82, 95% CI: 0.72-0.94). These results could help us identify vulnerable healthcare providers who need urgent mental care during the COVID-19 pandemic. Measures that may reduce psychological strain include adequate supply of medical resources, education on precautionary measures, and communication strategies to combat discrimination against frontline healthcare providers.

  33. Effects of infectious disease consultation and antimicrobial stewardship program at a Japanese cancer center: An interrupted time-series analysis. 国際誌

    Naoya Itoh, Nana Akazawa, Eri Kanawaku, Hiromi Murakami, Yuichi Ishibana, Daichi Kawamura, Takanori Kawabata, Keita Mori, Eiichi N Kodama, Norio Ohmagari

    PloS one 17 (1) e0263095 2022年

    DOI: 10.1371/journal.pone.0263095  

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    In cancer patients, appropriate diagnosis and management of infection are frequently challenging owing to subtle or atypical presentation. We investigated the effectiveness of infectious disease (ID) consultations and the Antimicrobial Stewardship Program (ASP) in a Japanese cancer center. This 36-month-period, single-institution, interrupted time series analysis was retrospectively conducted during April 1, 2018-March 31, 2021, to evaluate a two-phase intervention: Phase 1 (notification of antimicrobials by the infection control team) and Phase 2 (establishing an ID consultation service and implementing ASP). Among 32,202 patients hospitalized, 22,096 and 10,106 hospitalizations occurred at baseline and during intervention period, respectively. The Antimicrobial Stewardship Team (AST) provided feedback on specific broad-spectrum antimicrobials in 913 instances (347 appropriate [38%]; 566 inappropriate [62%]), and 440 ID consultations were completed, with a 75% overall acceptance rate for AST suggestions. In Phase 2, monthly carbapenem days of therapy (CAR-DOT) decreased significantly, and narrow-spectrum antibiotic usage increased significantly in both trend and level; monthly DOT of antipseudomonal agents decreased significantly in trend. The results of these analyses of antimicrobial use are consistent with the DOT-based data based on antimicrobial use density (AUD). The total number of inpatient specimens increased significantly; the trend of multidrug-resistant Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus infections decreased, without changes in the incidence of other resistant organisms, all-cause in-hospital mortality, and length of stay. Actual and adjusted CAR purchase costs per patient-day decreased without significant changes in the actual and adjusted purchase cost per patient-day for all intravenous antimicrobials. Combining ID consultation and ASP reduced carbapenem use without negative patient outcomes. Their implementation could facilitate establishment of safe cancer treatment facilities in Japan and improve prognosis in cancer patients.

  34. Association between fat mass index, fat-free mass index and hemoglobin A1c in a Japanese population: The Tohoku Medical Megabank Community-based Cohort Study.

    Masato Takase, Tomohiro Nakamura, Takumi Hirata, Naho Tsuchiya, Mana Kogure, Fumi Itabashi, Naoki Nakaya, Yohei Hamanaka, Junichi Sugawara, Kichiya Suzuki, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Journal of diabetes investigation 13 (5) 858-867 2021年12月3日

    DOI: 10.1111/jdi.13729  

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    AIMS/INTRODUCTION: Fat mass and fat-free mass affect glycated hemoglobin A1c (HbA1c) levels and blood glucose levels, respectively. The aim of the present study was to examine the association between the fat mass index and fat-free mass index with HbA1c. MATERIALS AND METHODS: We carried out a cross-sectional study that included 3,731 men and 9,191 women aged ≥20 years, living in Miyagi Prefecture, Japan, who were not treated for diabetes. The fat mass index and fat-free mass index were calculated as fat mass and fat-free mass divided by the height squared, respectively. The indices were classified into sex-specific quartiles and combined into 16 groups. An analysis of covariance was used to assess associations between the combined fat mass index and fat-free mass index with HbA1c adjusted for potential confounders. The linear trend test was carried out by stratifying the fat mass index and fat-free mass index, entering the number as a continuous term in the regression model. RESULTS: In multivariable models, a higher fat mass index was related to higher HbA1c levels in men and women in all fat-free mass index subgroups (P < 0.001 for linear trend). When we excluded the participants who had been identified as having diabetes, the fat-free mass index was also related to higher HbA1c levels in most fat mass index subgroups (P < 0.05 for linear trend). CONCLUSIONS: Fat mass index was positively related to HbA1c levels. The fat-free mass index was also related to HbA1c levels when we excluded participants who had been identified as having have diabetes.

  35. Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator. 国際誌

    Mitsuhiro Yamada, Ikuko N Motoike, Kaname Kojima, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Fumiki Katsuoka, Shu Tadaka, Matsuyuki Shirota, Miyuki Sakurai, Tomohiro Nakamura, Yohei Hamanaka, Kichiya Suzuki, Junichi Sugawara, Soichi Ogishima, Akira Uruno, Eiichi N Kodama, Naoya Fujino, Tadahisa Numakura, Tomohiro Ichikawa, Ayumi Mitsune, Takashi Ohe, Kengo Kinoshita, Masakazu Ichinose, Hisatoshi Sugiura, Masayuki Yamamoto

    Communications biology 4 (1) 1288-1288 2021年11月15日

    DOI: 10.1038/s42003-021-02813-8  

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    Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.

  36. Development of robust isothermal RNA amplification assay for lab-free testing of RNA viruses. 国際誌

    Radhika Biyani, Kirti Sharma, Kenji Kojima, Madhu Biyani, Vishnu Sharma, Tarun Kumawat, Kevin Maafu Juma, Itaru Yanagihara, Shinsuke Fujiwara, Eiichi Kodama, Yuzuru Takamura, Masahiro Takagi, Kiyoshi Yasukawa, Manish Biyani

    Scientific reports 11 (1) 15997-15997 2021年8月6日

    DOI: 10.1038/s41598-021-95411-x  

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    Simple tests of infectiousness that return results in minutes and directly from samples even with low viral loads could be a potential game-changer in the fight against COVID-19. Here, we describe an improved isothermal nucleic acid amplification assay, termed the RICCA (RNA Isothermal Co-assisted and Coupled Amplification) reaction, that consists of a simple one-pot format of 'sample-in and result-out' with a primary focus on the detection of low copy numbers of RNA virus directly from saliva without the need for laboratory processing. We demonstrate our assay by detecting 16S rRNA directly from E. coli cells with a sensitivity as low as 8 CFU/μL and RNA fragments from a synthetic template of SARS-CoV-2 with a sensitivity as low as 1740 copies/μL. We further demonstrate the applicability of our assay for real-time testing at the point of care by designing a closed format for paper-based lateral flow assay and detecting heat-inactivated SARS-COV-2 virus in human saliva at concentrations ranging from 28,000 to 2.8 copies/μL with a total assay time of 15-30 min.

  37. Association between the combined fat mass and fat-free mass index and hypertension: The Tohoku Medical Megabank Community-based Cohort Study. 国際誌

    Masato Takase, Tomohiro Nakamura, Naho Tsuchiya, Mana Kogure, Fumi Itabashi, Akira Narita, Takumi Hirata, Naoki Nakaya, Yohei Hamanaka, Junichi Sugawara, Kichiya Suzuki, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Clinical and experimental hypertension (New York, N.Y. : 1993) 43 (7) 1-12 2021年7月6日

    DOI: 10.1080/10641963.2021.1925681  

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    BACKGROUND: A  higher body fat percentage is associated with hypertension, even in non-obese individuals. The difference in body composition may be related to hypertension. The fat mass index (FMI) and fat-free mass index (FFMI) are proposed indicators of body composition. This study aimed to examine the relationship of a combination of FMI and FFMI with hypertension. METHODS: We conducted a cross-sectional study of 5,058 men and 11,842 women aged ≥ 20 years in the Miyagi Prefecture, northeastern Japan. The FMI and FFMI were calculated as the fat mass and fat-free mass divided by the height squared, respectively. The indices were classified into quartiles and combined into 16 groups. Hypertension was defined as casual blood pressure ≥ 140/90 mmHg and/or self-reported treatment for hypertension. Multivariable logistic regression models, adjusted for potential confounders, were used to assess the relationship of a combination of FMI and FFMI with hypertension. RESULTS: Higher FMI was associated with hypertension in most of the FFMI subgroups. Similarly, a higher FFMI was associated with hypertension in most of FMI subgroups. For men, the association between FFMI and hypertension in the lowest FMI group was not significant. CONCLUSIONS: Reducing the FMI and FFMI may be important in preventing hypertension. For men, the relationship between the FFMI and hypertension in the lowest FMI group might be weak.

  38. A Matched Case-Case-Control Study of the Impact of Clinical Outcomes and Risk Factors of Patients with IMP-Type Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae in Japan. 国際誌

    Sho Saito, Kayoko Hayakawa, Shinya Tsuzuki, Masahiro Ishikane, Maki Nagashima, Kazuhisa Mezaki, Yuko Sugiki, Taichi Tajima, Nobuaki Matsunaga, Satoshi Ide, Noriko Kinoshita, Yoshiki Kusama, Yumiko Fujitomo, Takato Nakamoto, Yuta Toda, Mitsuo Kaku, Eiichi N Kodama, Norio Ohmagari

    Antimicrobial agents and chemotherapy 65 (3) 2021年2月17日

    DOI: 10.1128/AAC.01483-20  

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    IMP-type carbapenemase, found in various Gram-negative bacteria, has been increasingly detected worldwide. We aimed to study the outcomes and risk factors for acquisition of IMP-type carbapenemase-producing carbapenem-resistant Enterobacteriaceae (IMP-CRE), as this has not been evaluated in detail. We conducted a matched case-case-control study of patients from whom IMP-CRE isolates were obtained. All patients who tested positive for IMP-CRE were included; they were matched with patients with carbapenem-susceptible Enterobacteriaceae (CSE) and with controls at a ratio of 1:1:2. The risk factors for acquisition for the CRE and CSE groups and mortality rates, which were calculated using multivariate logistic regression models with weighting according to the inverse probability of propensity scores, were compared. In total, 192 patients (96 patients each in the CRE and CSE groups, with 130 Enterobacter cloacae isolates and 62 Klebsiella sp. isolates) were included. The IMP-11 type was present in 43 patients, IMP-1 in 33, and IMP-60 and IMP-66 in 1 each; 31 patients with CRE (32.3%) and 34 with CSE (35.4%) developed infections. Multivariate analysis identified the following independent risk factors: gastrostomy, history of intravenous therapy or hemodialysis, and previous exposure to broad-spectrum β-lactam antibiotics, including penicillin with β-lactamase inhibitors, cephalosporins, and carbapenems. In propensity score-adjusted analysis, mortality rates for the CRE and CSE groups were similar (15.0% and 19.5%, respectively). We found that IMP-CRE may not contribute to worsened clinical outcomes, compared to CSE, and gastrostomy, previous intravenous therapy, hemodialysis, and broad-spectrum antimicrobial exposure were identified as risk factors for CRE isolation. Fluoroquinolone and aminoglycosides are potentially useful antibiotics for IMP-CRE infections.

  39. A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication. 国際誌

    Shin-Ichiro Hattori, Nobuyo Higashi-Kuwata, Hironori Hayashi, Srinivasa Rao Allu, Jakka Raghavaiah, Haydar Bulut, Debananda Das, Brandon J Anson, Emma K Lendy, Yuki Takamatsu, Nobutoki Takamune, Naoki Kishimoto, Kazutaka Murayama, Kazuya Hasegawa, Mi Li, David A Davis, Eiichi N Kodama, Robert Yarchoan, Alexander Wlodawer, Shogo Misumi, Andrew D Mesecar, Arun K Ghosh, Hiroaki Mitsuya

    Nature communications 12 (1) 668-668 2021年1月28日

    DOI: 10.1038/s41467-021-20900-6  

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    Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

  40. Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study.

    Atsushi Hozawa, Kozo Tanno, Naoki Nakaya, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Akira Narita, Mana Kogure, Kotaro Nochioka, Ryohei Sasaki, Nobuyuki Takanashi, Kotaro Otsuka, Kiyomi Sakata, Shinichi Kuriyama, Masahiro Kikuya, Osamu Tanabe, Junichi Sugawara, Kichiya Suzuki, Yoichi Suzuki, Eiichi N Kodama, Nobuo Fuse, Hideyasu Kiyomoto, Hiroaki Tomita, Akira Uruno, Yohei Hamanaka, Hirohito Metoki, Mami Ishikuro, Taku Obara, Tomoko Kobayashi, Kazuyuki Kitatani, Takako Takai-Igarashi, Soichi Ogishima, Mamoru Satoh, Hideki Ohmomo, Akito Tsuboi, Shinichi Egawa, Tadashi Ishii, Kiyoshi Ito, Sadayoshi Ito, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Masao Nagasaki, Kazuhiko Igarashi, Seizo Koshiba, Ritsuko Shimizu, Gen Tamiya, Keiko Nakayama, Hozumi Motohashi, Jun Yasuda, Atsushi Shimizu, Tsuyoshi Hachiya, Yuh Shiwa, Teiji Tominaga, Hiroshi Tanaka, Kotaro Oyama, Ryoichi Tanaka, Hiroshi Kawame, Akimune Fukushima, Yasushi Ishigaki, Tomoharu Tokutomi, Noriko Osumi, Tadao Kobayashi, Fuji Nagami, Hiroaki Hashizume, Tomohiko Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Ryujin Endo, Satoshi Nishizuka, Ichiro Tsuji, Jiro Hitomi, Motoyuki Nakamura, Kuniaki Ogasawara, Nobuo Yaegashi, Kengo Kinoshita, Shigeo Kure, Akio Sakai, Seiichiro Kobayashi, Kenji Sobue, Makoto Sasaki, Masayuki Yamamoto

    Journal of epidemiology 31 (1) 65-76 2021年1月5日

    DOI: 10.2188/jea.JE20190271  

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    BACKGROUND: We established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environment interactions on the incidence of major diseases, such as cancer and cardiovascular diseases. METHODS: We asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria were aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), such as carotid echography and calcaneal ultrasound bone mineral density. All participants agreed to measure genome information and to distribute their information widely. RESULTS: As a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants in the Type 1 survey were more likely to have psychological distress than those in the Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents, regardless of sex. CONCLUSION: This cohort comprised a large sample size and it contains information on the natural disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of the disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

  41. Implementation of evacuation measures during natural disasters under conditions of the novel coronavirus (COVID-19) pandemic based on a review of previous responses to complex disasters in Japan. 国際誌

    Masashi Sakamoto, Daisuke Sasaki, Yuichi Ono, Yuko Makino, Eiichi N Kodama

    Progress in disaster science 8 100127-100127 2020年12月

    DOI: 10.1016/j.pdisas.2020.100127  

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    We aimed to investigate how evacuation measures could be effectively implemented in the event of multiple disasters caused by natural hazards under conditions of the novel coronavirus infection (COVID-19) pandemic, which is rapidly spreading worldwide. We conducted a review of literature focusing on complex disasters, entailing natural disasters in combination of outbreaks or endemics of infectious diseases. Using the Google Scholar search engine, we identified and reviewed 24 papers sourced from academia, governments, and concerned organizations, and associated data on such disasters, commencing with the Great Hanshin-Awaji Earthquake, which occurred in 1995. In light of our review, we developed a summary of correspondences and problems linked to compound disasters involving conjunctions of outbreaks/endemics and natural disasters that could offer insights for developing measures to deal with natural disasters that occur in the context of the COVID-19 pandemic. We subsequently attempted to differentiate the characteristics of evacuation measures relating to COVID-19 from those relating to other infectious diseases using three sets of extracted keywords: (1) surveillance and information sharing, (2) evacuation center environment and stockpiled supplies, and (3) community disaster risk reduction and community leadership. We identified issues relating to evacuation measures that would need to be explored further to improve disaster management and preparedness in the future.

  42. 【新型コロナウイルス感染症(COVID-19)と精神科病院】宮城県精神科医療機関新型コロナウイルス感染症対策ネットワークにおける対策指針策定の経緯と意義 コロナ禍が精神医療にもたらした教訓

    富田 博秋, 佐藤 博俊, 角藤 芳久, 國井 泰人, 佐久間 篤, 牧野 祐子, 児玉 栄一, 徳田 浩一, 鈴木 陽, 吉田 眞紀子, 賀来 満夫, 押谷 仁, 小坂 健

    日本精神科病院協会雑誌 39 (11) 1125-1130 2020年11月

    出版者・発行元:(公社)日本精神科病院協会

    ISSN:1347-4103

  43. 【新型コロナウイルス感染症(COVID-19)と精神科病院】宮城県精神科医療機関新型コロナウイルス感染症対策ネットワークにおける対策指針策定の経緯と意義 コロナ禍が精神医療にもたらした教訓

    富田 博秋, 佐藤 博俊, 角藤 芳久, 國井 泰人, 佐久間 篤, 牧野 祐子, 児玉 栄一, 徳田 浩一, 鈴木 陽, 吉田 眞紀子, 賀来 満夫, 押谷 仁, 小坂 健

    日本精神科病院協会雑誌 39 (11) 1125-1130 2020年11月

    出版者・発行元:(公社)日本精神科病院協会

    ISSN:1347-4103

  44. Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

    Junichi Sugawara, Mami Ishikuro, Taku Obara, Tomomi Onuma, Keiko Murakami, Masahiro Kikuya, Fumihiko Ueno, Aoi Noda, Satoshi Mizuno, Tomoko Kobayashi, Yohei Hamanaka, Kichiya Suzuki, Eiichi Kodama, Naho Tsuchiya, Akira Uruno, Yoichi Suzuki, Osamu Tanabe, Hideyasu Kiyomoto, Akito Tsuboi, Atsushi Shimizu, Seizo Koshiba, Naoko Minegishi, Soichi Ogishima, Gen Tamiya, Hirohito Metoki, Atsushi Hozawa, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Shinichi Kuriyama, Masayuki Yamamoto

    Journal of epidemiology 32 (2) 69-79 2020年10月10日

    DOI: 10.2188/jea.JE20200338  

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    BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.

  45. Pyrimidine Analogues as a New Class of Gram-Positive Antibiotics, Mainly Targeting Thymineless-Death Related Proteins. 国際誌 査読有り

    Chihiro Oe, Hironori Hayashi, Kazushige Hirata, Kumi Kawaji, Fusako Hashima, Mina Sasano, Maaya Furuichi, Emiko Usui, Makoto Katsumi, Yasuhiko Suzuki, Chie Nakajima, Mitsuo Kaku, Eiichi N Kodama

    ACS infectious diseases 6 (6) 1490-1500 2020年6月12日

    DOI: 10.1021/acsinfecdis.9b00305  

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    Multidrug-resistant (MDR) bacteria are widespread throughout the world and pose an increasingly serious threat to human and animal health. Besides implementing strict measures to prevent improper antibiotic use, it remains essential that novel antibiotics must be developed. These antibiotics need to exert their activity via mechanisms different from those employed by currently approved antibiotics. In this study, we used several 5-fluorouracil (5-FU) analogues as chemical probes and investigated the potential of these pyrimidine analogues as antibacterial agents. Several 5-FU derivatives exerted potent activity against strains of Gram-positive cocci (GPC) that are susceptible or resistant toward approved antibiotics, without showing cross-resistance. Furthermore, we have provided evidence that the pyrimidine analogues exerted anti-GPC activity via thymineless death by inhibition of thymidylate synthetase (ThyA) and/or inhibition of RNA synthesis. Interestingly, whole genome resequencing of in vitro-selected, pyrimidine analogue-resistant Staphylococcus aureus mutants indicated that S. aureus strains with pyrimidine-analogue resistance induced an amino acid (AA) substitution, deletion, and/or insertion into thymineless-death related proteins except for ThyA, or enhanced the ThyA transcription level. Thus, S. aureus may avoid altering the ThyA function by introducing an AA substitution, suggesting that the pyrimidine analogues, which directly bind to ThyA without phosphorylation, may be more effective and show a higher genetic barrier than the pyrimidines that depend on phosphorylation for activity. The findings of this study may assist in the future development of a novel class of antibiotics for combating MDR GPC, including methicillin-resistant S. aureus and vancomycin-resistant Enterococci.

  46. Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project. 査読有り

    Akito Tsuboi, Hiroyuki Matsui, Naru Shiraishi, Takahisa Murakami, Akihito Otsuki, Junko Kawashima, Tomomi Kiyama, Toru Tamahara, Maki Goto, Shihoko Koyama, Junichi Sugawara, Eiichi N Kodama, Hirohito Metoki, Atsushi Hozawa, Shinichi Kuriyama, Hiroaki Tomita, Masahiro Kikuya, Naoko Minegishi, Kichiya Suzuki, Seizo Koshiba, Gen Tamiya, Nobuo Fuse, Yuichi Aoki, Takako Takai-Igarashi, Soichi Ogishima, Tomohiro Nakamura, Mika Sakurai-Yageta, Fuji Nagami, Kengo Kinoshita, Shigeo Kure, Ritsuko Shimizu, Keiichi Sasaki, Masayuki Yamamoto

    The Tohoku journal of experimental medicine 251 (2) 97-115 2020年6月

    DOI: 10.1620/tjem.251.97  

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    In order to assess the long-term impact of the Great East Japan Earthquake on the oral health of disaster victims and to evaluate gene-environmental interactions in the development of major oral diseases and oral-systemic associations, the oral part of two large-scale genome cohort studies by the Tohoku Medical Megabank Organization (ToMMo), including the Community-based cohort (CommCohort) study and the Birth and Three-Generation cohort (BirThree) study, have been conducted. The study population comprised 32,185 subjects, including 16,886 participants in the CommCohort study and 15,299 participants in the BirThree cohort study, recruited from 2013 to 2017. The oral studies consist of a questionnaire regarding oral hygiene behavior, clinical examinations by dentists, and oral plaque and saliva sampling for microbiome analyses, which were carried out at seven community support centers in Miyagi prefecture. The median age of all participants was 55.0 years, and 66.1% of participants were women. Almost all participants reported that they brushed their teeth more than once a day. The median number of present teeth was 27.0, and the decayed, missing and filled tooth number was 16.0, with a significant difference according to age and sex. The median periodontal pocket and clinical attachment level was 2.48 mm and 4.00 mm, respectively. Periodontal parameters increased significantly according to age, except for the accumulation of dental calculus. The oral part of these extensive cross-sectional studies provides a unique and important platform for future studies on oral health and diseases that elicit through interactions with systemic diseases, lifestyles, life events and genetic backgrounds, and contributes to researches clarifying the long-term effects of disasters on oral health.

  47. Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones. 国際誌 査読有り

    Kento Tsukada, Shono Shinki, Akiho Kaneko, Kazuma Murakami, Kazuhiro Irie, Masatoshi Murai, Hideto Miyoshi, Shingo Dan, Kumi Kawaji, Hironori Hayashi, Eiichi N Kodama, Aki Hori, Emil Salim, Takayuki Kuraishi, Naoya Hirata, Yasunari Kanda, Teigo Asai

    Nature communications 11 (1) 1830-1830 2020年4月14日

    DOI: 10.1038/s41467-020-15664-4  

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    A synthetic biology method based on heterologous biosynthesis coupled with genome mining is a promising approach for increasing the opportunities to rationally access natural product with novel structures and biological activities through total biosynthesis and combinatorial biosynthesis. Here, we demonstrate the advantage of the synthetic biology method to explore biological activity-related chemical space through the comprehensive heterologous biosynthesis of fungal decalin-containing diterpenoid pyrones (DDPs). Genome mining reveals putative DDP biosynthetic gene clusters distributed in five fungal genera. In addition, we design extended DDP pathways by combinatorial biosynthesis. In total, ten DDP pathways, including five native pathways, four extended pathways and one shunt pathway, are heterologously reconstituted in a genetically tractable heterologous host, Aspergillus oryzae, resulting in the production of 22 DDPs, including 15 new analogues. We also demonstrate the advantage of expanding the diversity of DDPs to probe various bioactive molecules through a wide range of biological evaluations.

  48. Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. 国際誌 査読有り

    Shinichi Kuriyama, Hirohito Metoki, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Masato Nagai, Hiroko Matsubara, Tomoko Kobayashi, Junichi Sugawara, Gen Tamiya, Atsushi Hozawa, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Akira Narita, Mana Kogure, Takumi Hirata, Ichiro Tsuji, Fuji Nagami, Nobuo Fuse, Tomohiko Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Yoichi Suzuki, Noriko Osumi, Keiko Nakayama, Kiyoshi Ito, Shinichi Egawa, Koichi Chida, Eiichi Kodama, Hideyasu Kiyomoto, Tadashi Ishii, Akito Tsuboi, Hiroaki Tomita, Yasuyuki Taki, Hiroshi Kawame, Kichiya Suzuki, Naoto Ishii, Soichi Ogishima, Satoshi Mizuno, Takako Takai-Igarashi, Naoko Minegishi, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Osamu Tanabe, Seizo Koshiba, Hiroaki Hashizume, Hozumi Motohashi, Teiji Tominaga, Sadayoshi Ito, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Jiro Hitomi, Makoto Sasaki, Kengo Kinoshita, Hiroshi Tanaka, Tadao Kobayashi, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

    International journal of epidemiology 49 (1) 18-19 2020年2月1日

    DOI: 10.1093/ije/dyz169  

    ISSN:0300-5771

  49. Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5. 国際誌

    Yoshitsugu Oikawa, Rumiko Izumi, Masashi Koide, Yoshihiro Hagiwara, Makoto Kanzaki, Naoki Suzuki, Koichi Kikuchi, Tetsuro Matsuhashi, Yukako Akiyama, Mariko Ichijo, Shun Watanabe, Takafumi Toyohara, Takehiro Suzuki, Eikan Mishima, Yasutoshi Akiyama, Yoshiaki Ogata, Chitose Suzuki, Hironori Hayashi, Eiichi N Kodama, Ken-Ichiro Hayashi, Eiji Itoi, Masashi Aoki, Shigeo Kure, Takaaki Abe

    PloS one 15 (12) e0231064 2020年

    DOI: 10.1371/journal.pone.0231064  

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    Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

  50. Application of human lymphoid cells for the evaluation of antivirals against human adenovirus type 19: Zalcitabine has superior activity compared to cidofovir

    Kohsuke Nakagawara, Hironori Hayashi, Kumi Kawaji, Mina Sasano, Eiichi N Kodama

    Antiviral Chemistry and Chemotherapy 28 204020662092131-204020662092131 2020年1月

    出版者・発行元:SAGE Publications

    DOI: 10.1177/2040206620921319  

    ISSN:2040-2066

    eISSN:2040-2066

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    Human adenovirus type 19 (HAdV-19) is a major cause of the epidemic keratoconjunctivitis. Outbreaks of keratoconjunctivitis are problematic to human health, especially for infants, the elderly, and immunocompromised individuals. However, the development of anti-HAdV drugs has been hampered by inconvenient screening systems; therefore, development of a simple screening method is highly desirable. In this study, we identified that HAdV-19 can infect a human lymphoid cell line transformed with human T-cell leukemia virus (MT-2 cells). MT-2 cells supported HAdV-19 replication and showed apparent cytopathic effects within five days post-infection. Using a thiazolyl blue tetrazolium bromide (MTT)-based colorimetric assay on MT-2 cells, we were able to detect the anti-HAdV-19 activities of previously reported nucleoside/tide compounds, including (S)-1–(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (cidofovir), 2′,3′-dideoxycytidine (zalcitabine) and 3′-deoxy-3′-fluorothymidine (trifluridine). Compared with previous methods, this system represents a more simple and rapid method to screen anti-HAdV-19 agents.

  51. 東日本大震災と熊本地震の比較分析による精神科病棟における被災時感染症対策の実態についての研究

    野崎 裕之, 児玉 栄一

    Japanese Journal of Disaster Medicine 24 (3) 392-392 2019年12月

    出版者・発行元:(一社)日本災害医学会

    ISSN:2189-4035

    eISSN:2434-4214

  52. Construction of a Meroterpenoid-Like Compounds Library Based on Diversity-Enhanced Extracts. 国際誌 査読有り

    Haruhisa Kikuchi, Kosuke Kawai, Yota Nakashiro, Takayuki Yonezawa, Kumi Kawaji, Eiichi N Kodama, Yoshiteru Oshima

    Chemistry (Weinheim an der Bergstrasse, Germany) 25 (4) 1106-1112 2019年1月18日

    DOI: 10.1002/chem.201805417  

    ISSN:0947-6539

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    The structural diversity of natural products and their derivatives have long contributed to the development of new drugs. However, the difficulty in obtaining compounds bearing skeletally novel structures has recently led to a decline of pharmaceutical research into natural products. This paper reports the construction of a meroterpenoid-like library containing 25 compounds with diverse molecular scaffolds obtained from diversity-enhanced extracts. This method constitutes an approach for increasing the chemical diversity of natural-product-like compounds by combining natural product chemistry and diversity-oriented synthesis. Extensive pharmacological screening of the library revealed promising compounds for anti-osteoporotic and anti-lymphoma/leukemia drugs. This result indicates that the use of diversity-enhanced extracts is an effective methodology for producing chemical libraries for the purpose of drug discovery.

  53. Identification of human immunodeficiency virus type-1 Gag-TSG101 interaction inhibitors by high-throughput screening. 国際誌 査読有り

    Lowela Siarot, Nopporn Chutiwitoonchai, Hirotaka Sato, Hao Chang, Hironori Sato, Masayuki Fujino, Tsutomu Murakami, Toshihiro Aono, Eiichi Kodama, Kazumichi Kuroda, Masami Takei, Yoko Aida

    Biochemical and biophysical research communications 503 (4) 2970-2976 2018年9月18日

    出版者・発行元:Elsevier BV

    DOI: 10.1016/j.bbrc.2018.08.079  

    ISSN:0006-291X

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    The interaction between viral protein Gag and cellular protein tumor susceptibility gene 101 (TSG101) is a crucial step in the HIV-1 replication cycle. This interaction initiates the viral assembly/budding via the cellular endosomal sorting complexes required for transport (ESCRT) pathway, making it a potential target for antiviral therapy. Here we developed a simple, robust, and reliable high-throughput screening (HTS) system based on enzyme-linked immunosorbent assay (ELISA) to identify compounds that inhibit HIV-1 replication by targeting Gag-TSG101 interaction. Through screening of the 9600-compound library using the established HTS system, several hit compounds, which inhibited Gag-TSG101 interaction, were identified. Subsequent assays revealed two hit compounds, HSM-9 and HSM-10, which have antiviral activity against CD4+ T cell-tropic NL4-3 and macrophage-tropic JR-CSF HIV-1 strains. These results suggest that our established HTS system is an indispensable tool for the identification of HIV-1 Gag-TSG101 interaction inhibitors.

  54. Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA). 国際誌 査読有り

    Zhe Li Salie, Karen A Kirby, Eleftherios Michailidis, Bruno Marchand, Kamalendra Singh, Lisa C Rohan, Eiichi N Kodama, Hiroaki Mitsuya, Michael A Parniak, Stefan G Sarafianos

    Proceedings of the National Academy of Sciences of the United States of America 113 (33) 9274-9 2016年8月16日

    出版者・発行元:NATL ACAD SCIENCES

    DOI: 10.1073/pnas.1605223113  

    ISSN:0027-8424

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    4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is the most potent nucleoside analog inhibitor of HIV reverse transcriptase (RT). It retains a 3'-OH yet acts as a chain-terminating agent by diminishing translocation from the pretranslocation nucleotide-binding site (N site) to the posttranslocation primer-binding site (P site). Also, facile misincorporation of EFdA-monophosphate (MP) results in difficult-to-extend mismatched primers. To understand the high potency and unusual inhibition mechanism of EFdA, we solved RT crystal structures (resolutions from 2.4 to 2.9 Å) that include inhibition intermediates (i) before inhibitor incorporation (catalytic complex, RT/DNA/EFdA-triphosphate), (ii) after incorporation of EFdA-MP followed by dT-MP (RT/DNAEFdA-MP(P)• dT-MP(N) ), or (iii) after incorporation of two EFdA-MPs (RT/DNAEFdA-MP(P)• EFdA-MP(N) ); (iv) the latter was also solved with EFdA-MP mismatched at the N site (RT/DNAEFdA-MP(P)• EFdA-MP(*N) ). We report that the inhibition mechanism and potency of EFdA stem from interactions of its 4'-ethynyl at a previously unexploited conserved hydrophobic pocket in the polymerase active site. The high resolution of the catalytic complex structure revealed a network of ordered water molecules at the polymerase active site that stabilize enzyme interactions with nucleotide and DNA substrates. Finally, decreased translocation results from favorable interactions of primer-terminating EFdA-MP at the pretranslocation site and unfavorable posttranslocation interactions that lead to observed localized primer distortions.

  55. A Novel Peptide Derived from the Fusion Protein Heptad Repeat Inhibits Replication of Subacute Sclerosing Panencephalitis Virus In Vitro and In Vivo. 国際誌 査読有り

    Masahiro Watanabe, Koichi Hashimoto, Yusaku Abe, Eiichi N Kodama, Ryota Nabika, Shinya Oishi, Shinichiro Ohara, Masatoki Sato, Yukihiko Kawasaki, Nobutaka Fujii, Mitsuaki Hosoya

    PloS one 11 (9) e0162823 2016年

    出版者・発行元:PUBLIC LIBRARY SCIENCE

    DOI: 10.1371/journal.pone.0162823  

    ISSN:1932-6203

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    Subacute sclerosing panencephalitis (SSPE) is a persistent, progressive, and fatal degenerative disease resulting from persistent measles virus (MV) infection of the central nervous system. Most drugs used to treat SSPE have been reported to have limited effects. Therefore, novel therapeutic strategies are urgently required. The SSPE virus, a variant MV strain, differs virologically from wild-type MV strain. One characteristic of the SSPE virus is its defective production of cell-free virus, which leaves cell-to-cell infection as the major mechanism of viral dissemination. The fusion protein plays an essential role in this cell-to-cell spread. It contains two critical heptad repeat regions that form a six-helix bundle in the trimer similar to most viral fusion proteins. In the case of human immunodeficiency virus type-1 (HIV-1), a synthetic peptide derived from the heptad repeat region of the fusion protein enfuvirtide inhibits viral replication and is clinically approved as an anti-HIV-1 agent. The heptad repeat regions of HIV-1 are structurally and functionally similar to those of the MV fusion protein. We therefore designed novel peptides derived from the fusion protein heptad repeat region of the MV and examined their effects on the measles and SSPE virus replication in vitro and in vivo. Some of these synthetic novel peptides demonstrated high antiviral activity against both the measles (Edmonston strain) and SSPE (Yamagata-1 strain) viruses at nanomolar concentrations with no cytotoxicity in vitro. In particular, intracranial administration of one of the synthetic peptides increased the survival rate from 0% to 67% in an SSPE virus-infected nude mouse model.

  56. A Cinnamon-Derived Procyanidin Compound Displays Anti-HIV-1 Activity by Blocking Heparan Sulfate- and Co-Receptor- Binding Sites on gp120 and Reverses T Cell Exhaustion via Impeding Tim-3 and PD-1 Upregulation. 国際誌 査読有り

    Bridgette Janine Connell, Sui-Yuan Chang, Ekambaranellore Prakash, Rahima Yousfi, Viswaraman Mohan, Wilfried Posch, Doris Wilflingseder, Christiane Moog, Eiichi N Kodama, Pascal Clayette, Hugues Lortat-Jacob

    PloS one 11 (10) e0165386 2016年

    出版者・発行元:PUBLIC LIBRARY SCIENCE

    DOI: 10.1371/journal.pone.0165386  

    ISSN:1932-6203

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    Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1-7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS) as well as to an antibody (mAb 17b) directed against the gp120 co-receptor binding site with an IC50 in the low μM range. IND02 has thus the remarkable property of simultaneously blocking gp120 binding to its major host cell surface counterparts. Additionally, the IND02-trimer impeded up-regulation of the inhibitory receptors Tim-3 and PD-1 on CD4+ and CD8+ cells, thereby demonstrating its beneficial effect by limiting T cell exhaustion. Among naturally derived products significantly inhibiting HIV-1, the IND02-trimer is the first component demonstrating an entry inhibition property through binding to the viral envelope glycoprotein. These data suggest that cinnamon, a widely consumed spice, could represent a novel and promising candidate for a cost-effective, natural entry inhibitor for HIV-1 which can also down-modulate T cell exhaustion markers Tim-3 and PD-1.

  57. Histone chaperone CAF-1 mediates repressive histone modifications to protect preimplantation mouse embryos from endogenous retrotransposons. 国際誌 査読有り

    Yuki Hatanaka, Kimiko Inoue, Mami Oikawa, Satoshi Kamimura, Narumi Ogonuki, Eiichi N Kodama, Yasuyuki Ohkawa, Yu-ichi Tsukada, Atsuo Ogura

    Proceedings of the National Academy of Sciences of the United States of America 112 (47) 14641-6 2015年11月24日

    出版者・発行元:NATL ACAD SCIENCES

    DOI: 10.1073/pnas.1512775112  

    ISSN:0027-8424

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    Substantial proportions of mammalian genomes comprise repetitive elements including endogenous retrotransposons. Although these play diverse roles during development, their appropriate silencing is critically important in maintaining genomic integrity in the host cells. The major mechanism for retrotransposon silencing is DNA methylation, but the wave of global DNA demethylation that occurs after fertilization renders preimplantation embryos exceptionally hypomethylated. Here, we show that hypomethylated preimplantation mouse embryos are protected from retrotransposons by repressive histone modifications mediated by the histone chaperone chromatin assembly factor 1 (CAF-1). We found that knockdown of CAF-1 with specific siRNA injections resulted in significant up-regulation of the retrotransposons long interspersed nuclear element 1, short interspersed nuclear element B2, and intracisternal A particle at the morula stage. Concomitantly, increased histone H2AX phosphorylation and developmental arrest of the majority (>95%) of embryos were observed. The latter was caused at least in part by derepression of retrotransposons, as treatment with reverse transcriptase inhibitors rescued some embryos. Importantly, ChIP analysis revealed that CAF-1 mediated the replacement of H3.3 with H3.1/3.2 at the retrotransposon regions. This replacement was associated with deposition of repressive histone marks, including trimethylation of histone H3 on lysine 9 (H3K9me3), H3K9me2, H3K27me3, and H4K20me3. Among them, H4K20me3 and H3K9me3 seemed to play predominant roles in retrotransposon silencing, as assessed by knockdown of specific histone methyltransferases and forced expression of unmethylatable mutants of H3.1K9 and H4K20. Our data thus indicate that CAF-1 is an essential guardian of the genome in preimplantation mouse embryos by deposition of repressive histone modifications via histone variant replacement.

  58. Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides. 国際誌 査読有り

    Teigo Asai, Kento Tsukada, Satomi Ise, Naoki Shirata, Makoto Hashimoto, Isao Fujii, Katsuya Gomi, Kosuke Nakagawara, Eiichi N Kodama, Yoshiteru Oshima

    Nature chemistry 7 (9) 737-43 2015年9月

    出版者・発行元:NATURE PUBLISHING GROUP

    DOI: 10.1038/nchem.2308  

    ISSN:1755-4330

    eISSN:1755-4349

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    The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.

  59. Inhibition of the DNA polymerase and RNase H activities of HIV-1 reverse transcriptase and HIV-1 replication by Brasenia schreberi (Junsai) and Petasites japonicus (Fuki) components. 査読有り

    Tetsuro Hisayoshi, Mayu Shinomura, Kanta Yokokawa, Ikumi Kuze, Atsushi Konishi, Kumi Kawaji, Eiichi N Kodama, Keishi Hata, Saori Takahashi, Satoru Nirasawa, Shohei Sakuda, Kiyoshi Yasukawa

    Journal of natural medicines 69 (3) 432-40 2015年7月

    出版者・発行元:SPRINGER JAPAN KK

    DOI: 10.1007/s11418-015-0885-9  

    ISSN:1340-3443

    eISSN:1861-0293

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    Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) possesses two distinct enzymatic activities: those of RNA- and DNA-dependent DNA polymerases and RNase H. In the current HIV-1 therapy, all HIV-1 RT inhibitors inhibit the activity of DNA polymerase, but not that of RNase H. We previously reported that ethanol and water extracts of Brasenia schreberi (Junsai) inhibited the DNA polymerase activity of HIV-1 RT [Hisayoshi et al. (2014) J Biol Macromol 14:59-65]. In this study, we screened 43 edible plants and found that ethanol and water extracts of Brasenia schreberi and water extract of Petasites japonicus strongly inhibit not only the activity of DNA polymerase to incorporate dTTP into poly(rA)-p(dT)15 but also the activity of RNase H to hydrolyze the RNA strand of an RNA/DNA hybrid. In addition, these three extracts inhibit HIV-1 replication in human cells, with EC50 values of 1-2 µg/ml. These results suggest that Brasenia schreberi and Petasites japonicus contain substances that block HIV-1 replication by inhibiting the DNA polymerase activity and/or RNase H activity of HIV-1 RT.

  60. Anti-HIV-1 activity determined by β-galactosidase activity in the multinuclear activation of an indicator assay is comparable with that by a conventional focus counting method. 国際誌 査読有り

    Miyamoto F, Kawaji K, Oishi S, Fujii N, Kaku M, Kodama EN

    Antiviral chemistry & chemotherapy 24 (2) 77-82 2015年4月

    出版者・発行元:None

    DOI: 10.1177/2040206615614164  

    ISSN:0956-3202

  61. Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor. 国際誌 査読有り

    Kyoji Hagiwara, Hideki Ishii, Tomoyuki Murakami, Shin-nosuke Takeshima, Nopporn Chutiwitoonchai, Eiichi N Kodama, Kumi Kawaji, Yasumitsu Kondoh, Kaori Honda, Hiroyuki Osada, Yasuko Tsunetsugu-Yokota, Masaaki Suzuki, Yoko Aida

    PloS one 10 (12) e0145573 2015年

    出版者・発行元:PUBLIC LIBRARY SCIENCE

    DOI: 10.1371/journal.pone.0145573  

    ISSN:1932-6203

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    The emergence of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus type 1 (HIV-1) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. We previously identified a potential parent compound, hematoxylin, which suppresses the nuclear import of HIV-1 via the Vpr-importin α interaction and inhibits HIV-1 replication in a Vpr-dependent manner by blocking nuclear import of the pre-integration complex. However, it was unstable. Here, we synthesized a stable derivative of hematoxylin that bound specifically and stably to Vpr and inhibited HIV-1 replication in macrophages. Furthermore, like hematoxylin, the derivative inhibited nuclear import of Vpr in an in vitro nuclear import assay, but had no effect on Vpr-induced G2/M phase cell cycle arrest or caspase activity. Interestingly, this derivative bound strongly to amino acid residues 54-74 within the C-terminal α-helical domain (αH3) of Vpr. These residues are highly conserved among different HIV strains, indicating that this region is a potential target for drug-resistant HIV-1 infection. Thus, we succeeded in developing a stable hematoxylin derivative that bound directly to Vpr, suggesting that specific inhibitors of the interaction between cells and viral accessory proteins may provide a new strategy for the treatment of HIV-1 infection.

  62. 4 '-Ethynyl-2-fluoro-2 '-deoxyadenosine (EFdA) Inhibits HIV-1 Reverse Transcriptase with Multiple Mechanisms 査読有り

    Eleftherios Michailidis, Andrew D. Huber, Emily M. Ryan, Yee T. Ong, Maxwell D. Leslie, Kayla B. Matzek, Kamalendra Singh, Bruno Marchand, Ariel N. Hagedorn, Karen A. Kirby, Lisa C. Rohan, Eiichi N. Kodama, Hiroaki Mitsuya, Michael A. Parniak, Stefan G. Sarafianos

    JOURNAL OF BIOLOGICAL CHEMISTRY 289 (35) 24533-24548 2014年8月

    出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI: 10.1074/jbc.M114.562694  

    ISSN:0021-9258

    eISSN:1083-351X

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    Background: 4-Ethynyl-2-fluoro-2-deoxyadenosine (EFdA) is a highly potent nucleoside analog reverse transcriptase (RT) inhibitor with a 3-OH. Results: EFdA inhibits RT as an immediate or delayed chain terminator depending on the DNA substrate sequence. RT efficiently misincorporates EFdA, producing non-extendable mismatched primers protected from excision. Conclusion: EFdA blocks RT by multiple mechanisms. Significance: Understanding the EFdA inhibition mechanism will help develop better antivirals. 4-Ethynyl-2-fluoro-2-deoxyadenosine (EFdA) is a nucleoside analog that, unlike approved anti-human immunodeficiency virus type 1 (HIV-1) nucleoside reverse transcriptase inhibitors, has a 3-OH and exhibits remarkable potency against wild-type and drug-resistant HIVs. EFdA triphosphate (EFdA-TP) is unique among nucleoside reverse transcriptase inhibitors because it inhibits HIV-1 reverse transcriptase (RT) with multiple mechanisms. (a) EFdA-TP can block RT as a translocation-defective RT inhibitor that dramatically slows DNA synthesis, acting as a de facto immediate chain terminator. Although non-translocated EFdA-MP-terminated primers can be unblocked, they can be efficiently converted back to the EFdA-MP-terminated form. (b) EFdA-TP can function as a delayed chain terminator, allowing incorporation of an additional dNTP before blocking DNA synthesis. In such cases, EFdA-MP-terminated primers are protected from excision. (c) EFdA-MP can be efficiently misincorporated by RT, leading to mismatched primers that are extremely hard to extend and are also protected from excision. The context of template sequence defines the relative contribution of each mechanism and affects the affinity of EFdA-MP for potential incorporation sites, explaining in part the lack of antagonism between EFdA and tenofovir. Changes in the type of nucleotide before EFdA-MP incorporation can alter its mechanism of inhibition from delayed chain terminator to immediate chain terminator. The versatility of EFdA in inhibiting HIV replication by multiple mechanisms may explain why resistance to EFdA is more difficult to emerge.

  63. エピジェネティックな二次代謝活性化法を利用するイチイ内生糸状菌からの新規生物活性物質の探索

    布木 純, 浅井 禎吾, 山下 幸和, 河治 久実, 児玉 栄一, 大島 吉輝

    日本薬学会年会要旨集 134年会 (2) 151-151 2014年3月

    出版者・発行元:(公社)日本薬学会

    ISSN:0918-9823

  64. Delayed emergence of HIV-1 variants resistant to4’-ethynyl-2-fluoro-2’-deoxyadenosine: comparative sequential passage studywith lamivudine, tenofovir, emtricitabineand BMS-986001. 査読有り

    Kenji Maeda, Darshan VDesai, Manabu Aoki, Hirotomo Nakata, Eiichi N Kodama, HiroakiMitsuya

    Antiviral Therapy 19 (2) 179-189 2014年

    出版者・発行元:None

    DOI: 10.3851/IMP2697  

    ISSN:1359-6535

  65. Effects of Substitutions at the 4 ' and 2 Positions on the Bioactivity of 4 '- Ethynyl-2-Fluoro-2 '-Deoxyadenosine

    Karen A. Kirby, Eleftherios Michailidis, Tracy L. Fetterly, Musetta A. Steinbach, Kamalendra Singh, Bruno Marchand, Maxwell D. Leslie, Ariel N. Hagedorn, Eiichi N. Kodama, Victor E. Marquez, Stephen H. Hughes, Hiroaki Mitsuya, Michael A. Parniak, Stefan G. Sarafianos

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 57 (12) 6254-6264 2013年12月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/AAC.01703-13  

    ISSN:0066-4804

    eISSN:1098-6596

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    Nucleos(t) ide reverse transcriptase inhibitors (NRTIs) form the backbone of most anti-HIV therapies. We have shown that 4 '-ethynyl- 2-fluoro-2 '-deoxyadenosine (EFdA) is a highly effective NRTI; however, the reasons for the potent antiviral activity of EFdA are not well understood. Here, we use a combination of structural, computational, and biochemical approaches to examine how substitutions in the sugar or adenine rings affect the incorporation of dA-based NRTIs like EFdA into DNA by HIV RT and their susceptibility to deamination by adenosine deaminase (ADA). Nuclear magnetic resonance (NMR) spectroscopy studies of 4 '-substituted NRTIs show that ethynyl or cyano groups stabilize the sugar ring in the C-2 '-exo/C-3 '-endo (north) conformation. Steady-state kinetic analysis of the incorporation of 4 '-substituted NRTIs by RT reveals a correlation between the north conformation of the NRTI sugar ring and efficiency of incorporation into the nascent DNA strand. Structural analysis and the kinetics of deamination by ADA demonstrate that 4 '-ethynyl and cyano substitutions decrease the susceptibility of adenosinebased compounds to ADA through steric interactions at the active site. However, the major determinant for decreased susceptibility to ADA is the 2-halo substitution, which alters the pK(a) of N1 on the adenine base. These results provide insight into how NRTI structural attributes affect their antiviral activities through their interactions with the RT and ADA active sites.

  66. Evaluation of Combinations of 4 '-Ethynyl-2-Fluoro-2 '-Deoxyadenosine with Clinically Used Antiretroviral Drugs 査読有り

    Atsuko Hachiya, Aaron B. Reeve, Bruno Marchand, Eleftherios Michailidis, Yee Tsuey Ong, Karen A. Kirby, Maxwell D. Leslie, Shinichi Oka, Eiichi N. Kodama, Lisa C. Rohan, Hiroaki Mitsuya, Michael A. Parniak, Stefan G. Sarafianos

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 57 (9) 4554-4583 2013年9月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/AAC.00283-13  

    ISSN:0066-4804

    eISSN:1098-6596

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    Drug combination studies of 4 '-ethynyl-2-fluoro-2 '-deoxyadenosine (EFdA) with FDA-approved drugs were evaluated by two different methods, MacSynergy II and CalcuSyn. Most of the combinations, including the combination of the two adenosine analogs EFdA and tenofovir, were essentially additive, without substantial antagonism or synergism. The combination of EFdA and rilpivirine showed apparent synergism. These studies provide information that may be useful for the design of EFdA combination regimens for initial and salvage therapy assessment.

  67. HIV-1 Resistance Mechanism to an Electrostatically Constrained Peptide Fusion Inhibitor That Is Active against T-20-Resistant Strains 査読有り

    Kazuki Shimane, Kumi Kawaji, Fusako Miyamoto, Shinya Oishi, Kentaro Watanabe, Yasuko Sakagami, Nobutaka Fujii, Kazuya Shimura, Masao Matsuoka, Mitsuo Kaku, Stefan G. Sarafianos, Eiichi N. Kodama

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 57 (8) 4035-4038 2013年8月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/AAC.00237-13  

    ISSN:0066-4804

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    T-20EK is a novel fusion inhibitor designed to have enhanced alpha-helicity over T-20 (enfuvirtide) through engineered electrostatic interactions between glutamic acid (E) and lysine (K) substitutions. T-20EK efficiently suppresses wild-type and T-20-resistant variants. Here, we selected T-20EK-resistant variants. A combination of L33S and N43K substitutions in gp41 were required for high resistance to T-20EK. While these substitutions also caused resistance to T-20, they did not cause cross-resistance to other known fusion inhibitors.

  68. Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA 査読有り

    Eleftherios Michailidis, Emily M. Ryan, Atsuko Hachiya, Karen A. Kirby, Bruno Marchand, Maxwell D. Leslie, Andrew D. Huber, Yee T. Ong, Jacob C. Jackson, Kamalendra Singh, Eiichi N. Kodama, Hiroaki Mitsuya, Michael A. Parniak, Stefan G. Sarafianos

    Retrovirology 10 (1) doi:10.1186/1742-4690-10-65-doi:10.1186/1742-4690-10-65 2013年6月24日

    DOI: 10.1186/1742-4690-10-65  

    ISSN:1742-4690

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    Background: The K65R substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is the major resistance mutation selected in patients treated with first-line antiretroviral tenofovir disoproxil fumarate (TDF). 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), is the most potent nucleoside analog RT inhibitor (NRTI) that unlike all approved NRTIs retains a 3'-hydroxyl group and has remarkable potency against wild-type (WT) and drug-resistant HIVs. EFdA acts primarily as a chain terminator by blocking translocation following its incorporation into the nascent DNA chain. EFdA is in preclinical development and its effect on clinically relevant drug resistant HIV strains is critically important for the design of optimal regimens prior to initiation of clinical trials.Results: Here we report that the K65R RT mutation causes hypersusceptibility to EFdA. Specifically, in single replication cycle experiments we found that EFdA blocks WT HIV ten times more efficiently than TDF. Under the same conditions K65R HIV was inhibited over 70 times more efficiently by EFdA than TDF. We determined the molecular mechanism of this hypersensitivity using enzymatic studies with WT and K65R RT. This substitution causes minor changes in the efficiency of EFdA incorporation with respect to the natural dATP substrate and also in the efficiency of RT translocation following incorporation of the inhibitor into the nascent DNA. However, a significant decrease in the excision efficiency of EFdA-MP from the 3' primer terminus appears to be the primary cause of increased susceptibility to the inhibitor. Notably, the effects of the mutation are DNA-sequence dependent.Conclusion: We have elucidated the mechanism of K65R HIV hypersusceptibility to EFdA. Our findings highlight the potential of EFdA to improve combination strategies against TDF-resistant HIV-1 strains. © 2013 Michailidis et al. licensee BioMed Central Ltd.

  69. Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design 査読有り

    Kazuki Izumi, Kumi Kawaji, Fusasko Miyamoto, Kazuki Shimane, Kazuya Shimura, Yasuko Sakagami, Toshio Hattori, Kentaro Watanabe, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka, Mitsuo Kaku, Stefan G. Sarafianos, Eiichi N. Kodama

    INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 45 (4) 908-915 2013年4月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.biocel.2013.01.015  

    ISSN:1357-2725

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    T-20 (enfuvirtide) resistance is caused by the N43D primary resistance mutation at its presumed binding site at the N-terminal heptad repeat (N-HR) of gp41, accompanied by the S138A secondary mutation at the C-terminal HR of gp41 (C-HR). We have discovered that modifying T-20 to include S138A (T-20(S138A)) allows it to efficiently block wild-type and T20-resistant viruses, by a mechanism that involves improved binding of T-20(S138A) to the N-HR that contains the N43D primary mutation. To determine how HIV-1 in turn escapes T-20(S138A) we used a dose escalation method to select T-20(S138A)-resistant HIV-1 starting with either wild-type (HIV-1(WT)) or T-20-resistant (HIV-1(N43D/S138A)) virus. We found that when starting with WT background, I37N and L44M emerged in the N-HR of gp41, and N126K in the C-HR. However, when starting with HIV-1(N43D/S138A), L33S and I69L emerged in N-HR, and E137K in C-HR. T-20(S138A)-resistant recombinant HIV-1 showed cross-resistance to other T-20 derivatives, but not to C34 derivatives, suggesting that T-20(S138A) suppressed HIV-1 replication by a similar mechanism to T-20. Furthermore, E137K enhanced viral replication kinetics and restored binding affinity with N-HR containing N43D, indicating that it acts as a secondary, compensatory mutation. We therefore introduced E137K into T-20(S138A) (T-20(E137K/S138A)) and revealed that T-20(E137K/S138A) moderately suppressed replication of T-20(S138A)-resistant HIV-1. T-20(E137K/S138A) retained activity to HIV-1 without L33S, which seems to be a key mutation for T-20 derivatives. Our data demonstrate that secondary mutations can be consistently used for the design of peptide inhibitors that block replication of HIV resistant to fusion inhibitors. (c) 2013 Elsevier Ltd. All rights reserved.

  70. Development of Small Molecule HIV-1 Fusion Inhibitors: Linking Biology to Chemistry 査読有り

    Fusako Miyamoto, Eiichi N. Kodama

    CURRENT PHARMACEUTICAL DESIGN 19 (10) 1827-1834 2013年3月

    出版者・発行元:BENTHAM SCIENCE PUBL LTD

    ISSN:1381-6128

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    Human immunodeficiency virus type 1 (HIV-1) primarily infects and then destroys CD4-positive lymphocytes, leading to the acquired immunodeficiency syndrome (AIDS). Over 20 drugs, most small and orally bioavailable, have been approved, and include reverse transcriptase and protease inhibitors. In 2003, the US-FDA approved enfuvirtide (T-20), a 36-amino acid peptide derived from the C-terminal heptad repeat of the HIV-1 gp41 ectodomain. T-20 was initially identified in 1992 from biological studies, and can effectively suppress HIV-1 infection with multi-drug resistance. Currently, numerous fusion inhibitory peptides have been designed and synthesized. Some of these peptides show strong inhibition even towards HIV-1 strains resistant to T-20. These developments also facilitate basic research into the mechanisms of HIV-1 fusion, because peptide inhibition resembles the process of viral fusion with the cellular membrane. In this review, we focus on HIV-1 fusion inhibitors and the application of their development and clinical findings to the concept of "biology to chemistry" to support rational drug design for small bioavailable compounds.

  71. HIV-1 Reverse Transcriptase (RT) Polymorphism 172K Suppresses the Effect of Clinically Relevant Drug Resistance Mutations to Both Nucleoside and Non-nucleoside RT Inhibitors 査読有り

    Atsuko Hachiya, Bruno Marchand, Karen A. Kirby, Eleftherios Michailidis, Xiongying Tu, Krzysztof Palczewski, Yee Tsuey Ong, Zhe Li, Daniel T. Griffin, Matthew M. Schuckmann, Junko Tanuma, Shinichi Oka, Kamalendra Singh, Eiichi N. Kodama, Stefan G. Sarafianos

    JOURNAL OF BIOLOGICAL CHEMISTRY 287 (35) 29988-29999 2012年8月

    出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI: 10.1074/jbc.M112.351551  

    ISSN:0021-9258

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    Polymorphisms have poorly understood effects on drug susceptibility and may affect the outcome of HIV treatment. We have discovered that an HIV-1 reverse transcriptase (RT) polymorphism (RT172K) is present in clinical samples and in widely used laboratory strains (BH10), and it profoundly affects HIV-1 susceptibility to both nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) when combined with certain mutations. Polymorphism 172K significantly suppressed zidovudine resistance caused by excision (e.g. thymidine-associated mutations) and not by discrimination mechanism mutations (e.g. Q151M complex). Moreover, it attenuated resistance to nevirapine or efavirenz imparted by NNRTI mutations. Although 172K favored RT-DNA binding at an excisable pre-translocation conformation, it decreased excision by thymidine-associated mutation-containing RT. 172K affected DNA handling and decreased RT processivity without significantly affecting the k(cat)/K-m values for dNTP. Surface plasmon resonance experiments revealed that RT172K decreased DNA binding by increasing the dissociation rate. Hence, the increased zidovudine susceptibility of RT172K results from its increased dissociation from the chain-terminated DNA and reduced primer unblocking. We solved a high resolution (2.15 angstrom) crystal structure of RT mutated at 172 and compared crystal structures of RT172R and RT172K bound to NNRTIs or DNA/dNTP. Our structural analyses high-light differences in the interactions between alpha-helix E (where 172 resides) and the active site beta 9-strand that involve the YMDD loop and the NNRTI binding pocket. Such changes may increase dissociation of DNA, thus suppressing excision-based NRTI resistance and also offset the effect of NNRTI resistance mutations thereby restoring NNRTI binding.

  72. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats 査読有り

    Xiaoguang Li, Hua Qian, Fusako Miyamoto, Takeshi Naito, Kumi Kawaji, Kazumi Kajiwara, Toshio Hattori, Masao Matsuoka, Kentaro Watanabe, Shinya Oishi, Nobutaka Fujii, Eiichi N. Kodama

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 424 (2) 257-261 2012年7月

    出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE

    DOI: 10.1016/j.bbrc.2012.06.097  

    ISSN:0006-291X

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    The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1(IIIB) and HIV-1(BaL) as representative CXGR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1(IIIB) activity, whereas fusion inhibitors showed both anti-HIV-1(IIIB) and anti-HIV-1(BaL) activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, "phenotypic drug evaluation", may be applicable for the evaluation of various antiviral drugs in vivo. (C) 2012 Elsevier Inc. All rights reserved.

  73. Development and application of fluorescent SDF-1 derivatives 査読有り

    Ryo Masuda, Shinya Oishi, Noriko Tanahara, Hiroaki Ohno, Akira Hirasawa, Gozoh Tsujimoto, Eiichi Kodama, Masao Matsuoka, Nobutaka Fujii

    Future Medicinal Chemistry 4 (7) 837-844 2012年5月

    DOI: 10.4155/fmc.12.31  

    ISSN:1756-8919 1756-8927

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    Background: SDF-1/CXCR4 signaling plays key roles in directed cell migration under physiological and pathological conditions. To develop agonist-based CXCR4 probes for detection of CXCR4 expression on cell lines and metastatic tumors, SAR analyses of fluorescent SDF-1 derivatives were carried out. Results: Several SDF-1 derivatives with a single fluorescent label were designed and synthesized. Modification of the SDF-1 C-terminus with AlexaFluor ® 488 or tetramethylrhodamine provided potent CXCR4 probes. Using a potent probe, a novel binding inhibition assay was established for biological evaluation of potential CXCR4 ligands. Conclusion: SDF-1 derivatives with C-terminal modification exhibit equipotent binding with CXCR4 and an alternative SDF-1 receptor CXCR7 to unlabeled SDF-1. The SDF-1 derivatives are applicable to flow cytometry to detect the receptor expression and identify binding compounds for CXCR4. © 2012 Future Science Ltd.

  74. In vitro and in vivo resistance to human immunodeficiency virus type 1 entry inhibitors 査読有り

    Yosuke Maeda, Kazuhisa Yoshimura, Fusako Miyamoto, Eiichi Kodama, Shigeyoshi Harada, Yuzhe Yuan, Shinji Harada, Keisuke Yusa

    Journal of AIDS and Clinical Research 3 (2) 2012年

    DOI: 10.4172/2155-6113.S2-004  

    ISSN:2155-6113

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    Viral entry is one of the most important targets for the efficient treatment of Human immunodeficiency virus type 1 (HIV-1)-infected patients. The entry process consists of multiple molecular steps: attachment of viral gp120 to CD4, interaction of gp120 with CCR5 or CXCR4 co-receptors, and gp41-mediated fusion of the viral and cellular membranes. Understanding the sequential steps of the entry process has enabled the production of various antiviral drugs to block each of these steps. Currently, the CCR5 inhibitor, maraviroc, and the fusion inhibitor, enfuvirtide, are clinically available. However, the emergence of HIV-1 strains resistant to entry inhibitors, as commonly observed for other classes of antiviral agents, is a serious problem. In this review, we describe a variety of entry inhibitors targeting different steps of viral entry and escape variants that are generated in vitro and in vivo. © 2011 Maeda R, et al.

  75. Potent anti-HIV-1 activity of N-HR-derived peptides including a deep pocket-forming region without antagonistic effects on T-20 査読有り

    Kazuki Izumi, Kentaro Watanabe, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka, Stefan G. Sarafanos, Eiichi N. Kodama

    Antiviral Chemistry and Chemotherapy 22 (1) 51-55 2012年

    DOI: 10.3851/IMP1836  

    ISSN:0956-3202

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    Background: Enfuvirtide (T-20), a C-terminal heptad repeat (C-HR)-derived peptide of HIV-1 glycoprotein, gp41, effectively suppresses HIV-1 replication through a putative mechanism that involves it acting as a decoy and binding to the N-terminal heptad repeat (N-HR) of the virus. In this study, we address whether the anti-HIV-1 activity of T-20 is antagonized by a variety of N-HR-de-rived peptides. Methods: Multinuclear activation of galactosidase indicator assays were used to evaluate T-20 activity in the presence of N-HR-derived peptides. The gp41-derived peptides were chemically synthesized. Results: We demonstrate additive anti-HIV activity when T-20 is used in combination with N-HR-derived pep-tides that do not have a putative binding region for the tryptophan-rich domain in T-20. The presence of a deep pocket-forming region in the N-HR-derived peptides enhanced their anti-HIV-1 activity, but had little effect on the activity of T-20. Conclusions: These results indicate that T-20-based antiviral therapies can be combined with N-HR-derived peptides. © 2011 International Medical Press.

  76. EFFECT OF TRANSLOCATION DEFECTIVE REVERSE TRANSCRIPTASE INHIBITORS ON THE ACTIVITY OF N348I, A CONNECTION SUBDOMAIN DRUG RESISTANT HIV-1 REVERSE TRANSCRIPTASE MUTANT 査読有り

    E. Michailidis, K. Singh, E. M. Ryan, A. Hachiya, Y. T. Ong, K. A. Kirby, B. Marchand, E. N. Kodama, H. Mitsuya, M. A. Parniak, S. G. Sarafianos

    CELLULAR AND MOLECULAR BIOLOGY 58 (1) 187-195 2012年

    出版者・発行元:C M B ASSOC

    DOI: 10.1170/T940  

    ISSN:0145-5680

    eISSN:1165-158X

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    4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a highly potent inhibitor of HIV-1 reverse transcriptase (RT). We have previously shown that its exceptional antiviral activity stems from a unique mechanism of action that is based primarily on blocking translocation of RT; therefore we named EFdA a Translocation Defective RT Inhibitor (TDRTI). The N348I mutation at the connection subdomain (CS) of HIV-1 RT confers clinically significant resistance to both nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). In this study we tested EFdA-triphosphate (TP) together with a related compound, ENdA-TP (4'-ethynyl-2-amino-2'-deoxyadenosine triphosphate) against HIV-1 RTs that carry clinically relevant drug resistance mutations: N348I, D67N/K70R/L210Q/T215F, D67N/K70R/L210Q/T215F/N348I, and A62V/V75I/F77L/F116Y/Q151M. We demonstrate that these enzymes remain susceptible to TDRTIs. Similar to WT RT, the N348I RT is inhibited by EFdA mainly at the point of incorporation through decreased translocation. In addition, the N348I substitution decreases the RNase H cleavage of DNA terminated with EFdA-MP (T/PEFdA-MP). Moreover, N348I RT unblocks EFdA-terminated primers with similar efficiency as the WT enzyme, and further enhances EFdA unblocking in the background of AZT-resistance mutations. This study provides biochemical insights into the mechanism of inhibition of N348I RT by TDRTIs and highlights the excellent efficacy of this class of inhibitors against WT and drug-resistant HIV-1 RTs.

  77. Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase 査読有り

    Tanyaradzwa P. Ndongwe, Adeyemi O. Adedeji, Eleftherios Michailidis, Yee Tsuey Ong, Atsuko Hachiya, Bruno Marchand, Emily M. Ryan, Devendra K. Rai, Karen A. Kirby, Angela S. Whatley, Donald H. Burke, Marc Johnson, Shilei Ding, Yi-Min Zheng, Shan-Lu Liu, Ei-Ichi Kodama, Krista A. Delviks-Frankenberry, Vinay K. Pathak, Hiroaki Mitsuya, Michael A. Parniak, Kamalendra Singh, Stefan G. Sarafianos

    NUCLEIC ACIDS RESEARCH 40 (1) 345-359 2012年1月

    出版者・発行元:OXFORD UNIV PRESS

    DOI: 10.1093/nar/gkr694  

    ISSN:0305-1048

    eISSN:1362-4962

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    We report key mechanistic differences between the reverse transcriptases (RT) of human immunodeficiency virus type-1 (HIV-1) and of xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus that can infect human cells. Steady and pre-steady state kinetics demonstrated that XMRV RT is significantly less efficient in DNA synthesis and in unblocking chain-terminated primers. Surface plasmon resonance experiments showed that the gammaretroviral enzyme has a remarkably higher dissociation rate (k(off)) from DNA, which also results in lower processivity than HIV-1 RT. Transient kinetics of mismatch incorporation revealed that XMRV RT has higher fidelity than HIV-1 RT. We identified RNA aptamers that potently inhibit XMRV, but not HIV-1 RT. XMRV RT is highly susceptible to some nucleoside RT inhibitors, including Translocation Deficient RT inhibitors, but not to non-nucleoside RT inhibitors. We demonstrated that XMRV RT mutants K103R and Q190M, which are equivalent to HIV-1 mutants that are resistant to tenofovir (K65R) and AZT (Q151M), are also resistant to the respective drugs, suggesting that XMRV can acquire resistance to these compounds through the decreased incorporation mechanism reported in HIV-1.

  78. K70Q Adds High-Level Tenofovir Resistance to "Q151M Complex" HIV Reverse Transcriptase through the Enhanced Discrimination Mechanism 査読有り

    Atsuko Hachiya, Eiichi N. Kodama, Matthew M. Schuckmann, Karen A. Kirby, Eleftherios Michailidis, Yasuko Sakagami, Shinichi Oka, Kamalendra Singh, Stefan G. Sarafianos

    PLOS ONE 6 (1) e16242-e16242 2011年1月

    出版者・発行元:PUBLIC LIBRARY SCIENCE

    DOI: 10.1371/journal.pone.0016242  

    ISSN:1932-6203

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    HIV-1 carrying the "Q151M complex" reverse transcriptase (RT) mutations (A62V/V75I/F77L/F116Y/Q151M, or Q151Mc) is resistant to many FDA-approved nucleoside RT inhibitors (NRTIs), but has been considered susceptible to tenofovir disoproxil fumarate (TFV-DF or TDF). We have isolated from a TFV-DF-treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient&apos;s therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations.

  79. THE SUGAR RING CONFORMATION OF 4 '-ETHYNYL-2-FLUORO-2 '-DEOXYADENOSINE AND ITS RECOGNITION BY THE POLYMERASE ACTIVE SITE OF HIV REVERSE TRANSCRIPTASE 査読有り

    K. A. Kirby, K. Singh, E. Michailidis, B. Marchand, E. N. Kodama, N. Ashida, H. Mitsuya, M. A. Parniak, S. G. Sarafianos

    CELLULAR AND MOLECULAR BIOLOGY 57 (1) 40-46 2011年

    出版者・発行元:C M B ASSOC

    DOI: 10.1170/T900  

    ISSN:0145-5680

    eISSN:1165-158X

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    4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is the most potent inhibitor of HIV reverse transcriptase (RT). We have recently named EFdA a Translocation Defective RT Inhibitor (TDRTI) because after its incorporation in the nucleic acid it blocks DNA polymerization, primarily by preventing translocation of RT on the template/primer that has EFdA at the 3'-primer end (T/P-EFdA). The sugar ring conformation of EFdA may also influence RT inhibition by a) affecting the binding of EFdA triphosphate (EFdATP) at the RT active site and/or b) by preventing proper positioning of the 3'-OH of EFdA in T/P-EFdA that is required for efficient DNA synthesis. Specifically, the North (C2'-exo/C3'-endo), but not the South (C2'-endo/C3'-exo) nucleotide sugar ring conformation is required for efficient binding at the primer-binding and polymerase active sites of RT. In this study we use nuclear magnetic resonance (NMR) spectroscopy experiments to determine the sugar ring conformation of EFdA. We find that unlike adenosine nucleosides unsubstituted at the 4'-position, the sugar ring of EFdA is primarily in the North conformation. This difference in sugar ring puckering likely contributes to the more efficient incorporation of EFdATP by RT than dATP. In addition, it suggests that the 3'-OH of EFdA in T/P-EFdA is not likely to prevent incorporation of additional nucleotides and thus it does not contribute to the mechanism of RT inhibition. This study provides the first insights into how structural attributes of EFdA affect its antiviral potency through interactions with its RT target.

  80. Epigallocatechin gallate inhibits the HIV reverse transcription step 査読有り

    Shenwei Li, Toshio Hattori, Eiichi N. Kodama

    Antiviral Chemistry and Chemotherapy 21 (6) 239-243 2011年

    DOI: 10.3851/IMP1774  

    ISSN:0956-3202

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    Background: Epigallocatechin gallate (EGCG), the most abundant catechin in green tea, has been reported to inhibit HIV-1 replication prior to its integration into host DNA via various proposed mechanisms however, the specific main target(s) of EGCG remain unclear. In this study, we investigated a number of these proposed detailed mechanism(s) using a cell-based model. Methods: Multinuclear activation of galactosidase indicator assays were used for all experiments, including examination of the time of addition and the synergisms with a nucleoside reverse transcriptase inhibitor, 3′-azido-3′-deoxythymidine (AZT). Results: The experiments revealed that EGCG suppressed both HIV-1 IIIB and HIV-2 EHO infection in HeLa-CD4-LTR-β- gal cells, with relatively low 50% effective concentrations of 1.6 and 2.0 μM, respectively. The inhibitory profile of EGCG generated using a time-of-addition assay was identical to that of a non-nucleoside reverse transcriptase inhibitor (NNRTI), MKC-442. Furthermore, synergistic inhibition was observed in EGCG with AZT. Conclusions: Based on our findings, EGCG appears to act mainly as an allosteric reverse transcriptase inhibitor with mechanisms different from those of currently approved NNRTIs that directly interact with the NNRTI binding pocket. Thus, EGCG is a good candidate for use as an additional or supportive anti-HIV agent derived from natural plants. © 2011 International Medical Press.

  81. The N348I Mutation at the Connection Subdomain of HIV-1 Reverse Transcriptase Decreases Binding to Nevirapine 査読有り

    Matthew M. Schuckmann, Bruno Marchand, Atsuko Hachiya, Eiichi N. Kodama, Karen A. Kirby, Kamalendra Singh, Stefan G. Sarafianos

    JOURNAL OF BIOLOGICAL CHEMISTRY 285 (49) 38700-38709 2010年12月

    出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI: 10.1074/jbc.M110.153783  

    ISSN:0021-9258

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    The N348I mutation at the connection subdomain of HIV-1 reverse transcriptase (RT) confers clinically significant resistance to both nucleoside and non-nucleoside RT inhibitors (NNRTIs) by mechanisms that are not well understood. We used transient kinetics to characterize the enzymatic properties of N348I RT and determine the biochemical mechanism of resistance to the NNRTI nevirapine (NVP). We demonstrate that changes distant from the NNRTI binding pocket decrease inhibitor binding (increase K(d-NVP)) by primarily decreasing the association rate of the inhibitor (k(on-NVP)). We characterized RTs mutated in either p66 (p66(N348I)/p51(WT)), p51 (p66(WT)/p51(N348I)), or both subunits (p66(N348I)/p51(N348I)). Mutation in either subunit caused NVP resistance during RNA-dependent and DNA-dependent DNA polymerization. Mutation in p66 alone (p66(N348I)/p51(WT)) caused NVP resistance without significantly affecting RNase H activity, whereas mutation in p51 caused NVP resistance and impaired RNase H, demonstrating that NVP resistance may occur independently from defects in RNase H function. Mutation in either subunit improved affinity for nucleic acid and enhanced processivity of DNA synthesis. Surprisingly, mutation in either subunit decreased catalytic rates (k(pol)) of p66(N348I)/p51(N348I), p66(N348I)/p51(WT), and p66(WT)/p51(N348I) without significantly affecting affinity for deoxynucleotide substrate (K(d-dNTP)). Hence, in addition to providing structural integrity for the heterodimer, p51 is critical for fine tuning catalytic turnover, RNase H processing, and drug resistance. In conclusion, connection subdomain mutation N348I decreases catalytic efficiency and causes in vitro resistance to NVP by decreasing inhibitor binding.

  82. Resistance Profiles of Novel Electrostatically Constrained HIV-1 Fusion Inhibitors 査読有り

    Kazuya Shimura, Daisuke Nameki, Keiko Kajiwara, Kentaro Watanabe, Yasuko Sakagami, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka, Stefan G. Sarafianos, Eiichi N. Kodama

    JOURNAL OF BIOLOGICAL CHEMISTRY 285 (50) 39471-39480 2010年12月

    出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI: 10.1074/jbc.M110.145789  

    ISSN:0021-9258

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    Human immunodeficiency virus (HIV) gp41 plays a key role in viral fusion; the N- and C-terminal heptad repeats (N-HR and C-HR) of gp41 form a stable 6-helical conformation for fusion. Therefore, HR-derived peptides, such as enfuvirtide (T-20), inhibit HIV-1 fusion by acting as decoys, and have been used for the treatment of HIV-1 infection. However, the efficacy of T-20 is attenuated by resistance mutations in gp41, including V38A and N43D. To suppress the resistant variants, we previously developed electrostatically constrained peptides, SC34 and SC34EK, and showed that both exhibited potent anti-HIV-1 activity against wild-type and T-20-resistant variants. In this study, to clarify the resistance mechanism to this next generation of fusion inhibitors, we selected variants with resistance to SC34 and SC34EK in vitro. The resistant variants had multiple mutations in gp41. All of these mutations individually caused less than 6-fold resistance to SC34 and SC34EK, indicating that there is a significant genetic barrier for high-level resistance. Cross-resistance to SC34 and SC34EK was reduced by a simple difference in the polarity of two intramolecular electrostatic pairs. Furthermore, the selected mutations enhanced the physicochemical interactions with N-HR variants and restored activities of the parental peptide, C34, even to resistant variants. These results demonstrate that our approach of designing gp41-binding inhibitors using electrostatic constraints and information derived from resistance studies produces inhibitors with enhanced activity, high genetic barrier, and distinct resistance profile from T-20 and other inhibitors. Hence, this is a promising approach for the design of future generation peptide fusion inhibitors.

  83. Affinity selection and sequence-activity relationships of HIV-1 membrane fusion inhibitors directed at the drug-resistant variants 査読有り

    Shinya Oishi, Kentaro Watanabe, Saori Ito, Michinori Tanaka, Hiroki Nishikawa, Hiroaki Ohno, Kazuki Shimane, Kazuki Izumi, Yasuko Sakagami, Eiichi N. Kodama, Masao Matsuoka, Akira Asai, Nobutaka Fujii

    MEDCHEMCOMM 1 (4) 276-281 2010年10月

    出版者・発行元:ROYAL SOC CHEMISTRY

    DOI: 10.1039/c0md00091d  

    ISSN:2040-2503

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    Enfuvirtide is the first approved membrane fusion inhibitor against HIV-1. Although this drug is effective against multi-drug resistant strains, the emergence of enfuvirtide-resistant strains has been reported in patients who have received an enfuvirtide-containing regimen. Based on the high affinity of synthetic HIV-1 gp41 C-terminal heptad repeat (C-HR) peptides to the counterpart trimeric N-terminal heptad repeat (N-HR) coiled-coil structure, a novel screening approach has been established to facilitate the identification of potent fusion inhibitors against wild-type and enfuvirtide-resistant HIV-1. In this process, affinity selection using histidine-tagged N-HR peptides with the sequences derived from wild-type and resistant strains efficiently captured potent inhibitory peptides from a pool of highly water-soluble C-HR peptides with a-helix-inducible motifs. A highly potent peptide was found from a single amino acid substitution observed in an enfuvirtide-resistant variant as well as peptides with unprecedented modifications at the mutated site.

  84. Rev-derived peptides inhibit HIV-1 replication by antagonism of Rev and a co-receptor, CXCR4 査読有り

    Kazuki Shimane, Eiichi N. Kodama, Ikuhiko Nakase, Shiroh Futaki, Yasuteru Sakurai, Yasuko Sakagami, Xiaoguang Li, Toshio Hattori, Stefan G. Sarafianos, Masao Matsuoka

    INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 42 (9) 1482-1488 2010年9月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.biocel.2010.05.005  

    ISSN:1357-2725

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    Rev, a viral regulatory protein of HIV-1, binds through its arginine-rich domain to the Rev-responsive element (RRE), a secondary structure in transcribed HIV-1 RNA. Binding of Rev to RRE mediates export of singly spliced or unspliced mRNAs from the nucleus to the cytoplasm. It has been previously shown that a certain arginine-rich peptide exhibits not only RRE-binding ability but also cell permeability and antagonism of CXCR4, one of the major coreceptors of HIV-1. Here we designed and synthesized arginine-rich peptides derived from the RNA-binding domain of Rev (Rev(34-50)) and evaluated their anti-HIV-1 activities. Rev(34-50)-A(4)C, comprising Rev(34-50) with AAAAC at the C-terminus to increase the alpha-helicity. inhibited HIV-1 entry by CXCR4 antagonism and virus production in persistently HIV-1-infected PM1-CCR5 cells. Interestingly, similar motif of human lymphotropic virus type I Rex (Rex(1-21)) also exerted moderate anti-HIV-1 activity. These results indicate that arginine-rich peptide, Rev(34-50)-A(4)C exerts dual antagonism against CXCR4 and Rev. (C) 2010 Elsevier Ltd. All rights reserved.

  85. Characterization of HIV-1 resistance to a fusion inhibitor, N36, derived from the gp41 amino-terminal heptad repeat 査読有り

    Kazuki Izumi, Shota Nakamura, Hiroaki Nakano, Kazuya Shimura, Yasuko Sakagami, Shinya Oishi, Susumu Uchiyama, Tadayasu Ohkubo, Yuji Kobayashi, Nobutaka Fujii, Masao Matsuoka, Eiichi N. Kodama

    ANTIVIRAL RESEARCH 87 (2) 179-186 2010年8月

    出版者・発行元:ELSEVIER SCIENCE BV

    DOI: 10.1016/j.antiviral.2010.04.011  

    ISSN:0166-3542

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    A transmembrane glycoprotein of HIV-1, gp41, plays a central role in membrane fusion of HIV-1 and host cells. Peptides derived from the amino- and carboxyl-terminal heptad repeat (N-HR and C-HR, respectively) of gp41 inhibit this fusion. The mechanism of resistance to enfuvirtide, a C-HR-derived peptide, is well defined; however the mechanism of resistance to N-HR-derived peptides remains unclear. We characterized an HIV-1 isolate resistant to the N-HR-derived peptide, N36. This HIV-1 acquired a total of four amino acid substitutions, D36G, N126K and E137Q in gp41, and P183Q in gp120. Among these substitutions, N126K and/or E137Qconferred resistance to not only N36, but also C34, which is the corresponding C-HR-derived peptide fusion inhibitor. We performed crystallographic and biochemical analysis of the 6-helix bundle formed by synthetic gp41-derived peptides containing the N126K/E137Q substitutions. The structure of the 6-helix bundle with N126K/E137Qwas identical to that in wild-type HIV-1 except for the presence of a new hydrogen bond. Denaturing experiments revealed that the stability of the 6-helix bundle of N126K/E137Q is greater than in the wild-type. These results suggest that the stabilizing effect of N126K/E137Q provides resistance to N36 and C34. (C) 2010 Elsevier B.V. All rights reserved.

  86. Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres 査読有り

    Tetsuo Narumi, Ryoko Hayashi, Kenji Tomita, Kazuya Kobayashi, Noriko Tanahara, Hiroaki Ohno, Takeshi Naito, Eiichi Kodama, Masao Matsuoka, Shinya Oishi, Nobutaka Fujii

    ORGANIC & BIOMOLECULAR CHEMISTRY 8 (3) 616-621 2010年

    出版者・発行元:ROYAL SOC CHEMISTRY

    DOI: 10.1039/b917236j  

    ISSN:1477-0520

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    A set of cyclic peptide analogues of a selective CXCR4 antagonist FC131 [cyclo(-D-Tyr-Arg-Arg-Nal-Gly-)] were synthesized and bioevaluated. Using (E)-alkene and (Z)-fluoroalkene dipeptide isosteres for Arg-Arg and Arg-Nal substructures, indispensable or the partial contribution of the two peptide bonds to the CXCR4 antagonism and anti-HIV activity was demonstrated. FC131 and the analogues were shown to selectively inhibit SDF-1 binding to CXCR4, whereas no inhibition of binding of SDF-1 to CXCR7 was observed.

  87. Procyanidin B1 purified from Cinnamomi cortex suppresses hepatitis C virus replication 査読有り

    Shenwei Li, Eiichi N. Kodama, Yuuki Inoue, Hideki Tani, Yoshiharu Matsuura, Jing Zhang, Takashi Tanaka, Toshio Hattori

    Antiviral Chemistry and Chemotherapy 20 (6) 239-248 2010年

    DOI: 10.3851/IMP1597  

    ISSN:0956-3202

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    Background: A combination of pegylated interferon and ribavirin is the current standard therapy for hepatitis C virus (HCV) infection, but this combination provides relatively low efficacy, especially in some patients with HCV genotype 1 infection therefore, the development of novel therapeutic agents is required for further improvement in the treatment of chronic HCV infection. Methods: HCV pseudotype and subgenomic replicon assays were used in this study. The interaction of compounds with HCV receptors was examined using flow cytometry. Intracellular RNA levels were determined by semi-quantitative reverse transcriptase PCR. Results: Procyanidin B1 (PB1), a dimer of (-)- epicatechin and (+)-catechin, purified from Cinnamomi cortex, inhibits infection by vesicular stomatitis virus and HCV pseudotype virus in Huh-7 cells, with 50% effective concentrations of 29 and 15 μM, respectively. No inhibitory effects were observed in each component of PB1. We found that PB1 does not interfere with viral entry or receptor expression, but inhibits HCV RNA synthesis in a dose-dependent manner. Conclusions: These results indicate that PB1 suppresses HCV RNA synthesis, possibly as a HCV RNA polymerase inhibitor. Our results might contribute towards the development of more effective inhibitors for HCV infection from natural plants. ©2010 International Medical Press.

  88. Binding of Multivalent Anionic Porphyrins to V3 Loop Fragments of an HIV-1 Envelope and Their Antiviral Activity 査読有り

    Kenji Watanabe, Shigeru Negi, Yukio Sugiura, Akiko Kiriyama, Akino Honbo, Katsumi Iga, Eiichi N. Kodama, Takeshi Naitoh, Masao Matsuoka, Koji Kano

    CHEMISTRY-AN ASIAN JOURNAL 5 (4) 825-834 2010年

    出版者・発行元:WILEY-V C H VERLAG GMBH

    DOI: 10.1002/asia.200900465  

    ISSN:1861-4728

    eISSN:1861-471X

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    Interactions of multivalent anionic porphyrins and their iron(III) complexes with cationic peptides. V3(Ba)-L and V3(IIIB), which correspond to those of the V3 loop regions of the gp120 envelope proteins of the HIV-1(Ba-L) and HIV-1(IIIB) strains, respectively, are studied by UV/Vis, circular dichroism. (1)H NMR, and EPR spectroscopy, a microcalorimetric titration method, and anti-HIV assays. Tetrakis(3,5-dicarboxylatophenyl)porphyrin (P1), tetrakis[4(3,5-dicarboxylatophenylmethoxy)phenyl]porphyrin (P2), and their ferric complexes (Fe (III)P1 and Fe(III)P2) were used as the multivalent anionic porphyrins. PI and Fe(III)P1 formed stable complexes with both V3 peptides (binding constant K &gt; 10(6) M(-1)) through combined electrostatic and van der Waals interactions. Coordination of the His residues in V3(Ba-L) to the iron center of Fe(III)P1 also played an important role in the complex stabilization. As P2 and Fe(III)P2 form self-aggregates in aqueous solution even at low concentrations, detailed analysis of their interactions with the V3 peptides could not be performed. To ascertain whether the results obtained in the model system are applicable to a real biological system, anti-HIV-1(BA-L) and HIV-1(IIIB) activity of the porphyrins is exam ined by multiple nuclear activation of a galactosidase indicator (MAGI) and 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- tetrazolium bromide (MTT) assays. There is little correlation between chemical analysis and actual anti-HIV activity, and the size rather than the number of the anionic groups of the porphyrin is important for anti-HIV activity. All the porphyrins show high selectivity, low cytotoxicity. and high viral activity. Fe(III)P1 and Fe(III)P2 are used for the pharmacokinetic study. Half-lives of these iron porphyrins in serum of male Wistar rats are around 4 to 6 h owing to strong interaction of these porphyrins with serum albumin.

  89. Bioorganic synthesis of a recombinant HIV-1 fusion inhibitor, SC35EK, with an N-terminal pyroglutamate capping group 査読有り

    Kazumi Kajiwara, Kentaro Watanabe, Rei Tokiwa, Tomoko Kurose, Hiroaki Ohno, Hiroko Tsutsumi, Yoji Hata, Kazuki Izumi, Eiichi Kodama, Masao Matsuoka, Shinya Oishi, Nobutaka Fujii

    BIOORGANIC & MEDICINAL CHEMISTRY 17 (23) 7964-7970 2009年12月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2009.10.017  

    ISSN:0968-0896

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    The bioorganic synthesis of an end-capped anti-HIV peptide from a recombinant protein was investigated. Cyanogen bromide-mediated cleavage of two Met-Gln sites across the target anti-HIV sequence generated an HIV-1 fusion inhibitor (SC35EK) analog bearing an N-terminal pyroglutamate (pGlu) residue and a C-terminal homoserine lactone (Hsl) residue. The end-capped peptide, pGlu-SC35EK-Hsl, had similar bioactivity and biophysical properties to the parent peptide, and an improved resistance to peptidase-mediated degradation was observed compared with the non-end-capped peptide obtained using standard recombinant technology. (c) 2009 Elsevier Ltd. All rights reserved.

  90. Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4 '-Ethynyl-2-fluoro-2 '-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor 査読有り

    Eleftherios Michailidis, Bruno Marchand, Eiichi N. Kodama, Kamlendra Singh, Masao Matsuoka, Karen A. Kirby, Emily M. Ryan, Ali M. Sawani, Eva Nagy, Noriyuki Ashida, Hiroaki Mitsuya, Michael A. Parniak, Stefan G. Sarafianos

    JOURNAL OF BIOLOGICAL CHEMISTRY 284 (51) 35681-35691 2009年12月

    出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI: 10.1074/jbc.M109.036616  

    ISSN:0021-9258

    eISSN:1083-351X

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    Nucleoside reverse transcriptase inhibitors (NRTIs) are employed in first line therapies for the treatment of human immunodeficiency virus (HIV) infection. They generally lack a 3'-hydroxyl group, and thus when incorporated into the nascent DNA they prevent further elongation. In this report we show that 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), a nucleoside analog that retains a 3'-hydroxyl moiety, inhibited HIV-1 replication in activated peripheral blood mononuclear cells with an EC50 of 0.05 nM, a potency several orders of magnitude better than any of the current clinically used NRTIs. This exceptional antiviral activity stems in part from a mechanism of action that is different from approved NRTIs. Reverse transcriptase (RT) can use EFdA-5'-triphosphate (EFdA-TP) as a substrate more efficiently than the natural substrate, dATP. Importantly, despite the presence of a 3'-hydroxyl, the incorporated EFdA monophosphate (EFdA-MP) acted mainly as a de facto terminator of further RT-catalyzed DNA synthesis because of the difficulty of RT translocation on the nucleic acid primer possessing 3'-terminal EFdA-MP. EFdA-TP is thus a translocation-defective RT inhibitor (TDRTI). This diminished translocation kept the primer 3'-terminal EFdA-MP ideally located to undergo phosphorolytic excision. However, net phosphorolysis was not substantially increased, because of the apparently facile reincorporation of the newly excised EFdA-TP. Our molecular modeling studies suggest that the 4'-ethynyl fits into a hydrophobic pocket defined by RT residues Ala-114, Tyr-115, Phe-160, and Met-184 and the aliphatic chain of Asp-185. These interactions, which contribute to both enhanced RT utilization of EFdA-TP and difficulty in the translocation of 3'-terminal EFdA-MP primers, underlie the mechanism of action of this potent antiviral nucleoside.

  91. Bioorganic synthesis of end-capped anti-HIV peptides by simultaneous cyanocysteine-mediated cleavages of recombinant proteins 査読有り

    Michinori Tanaka, Kazumi Kajiwara, Rei Tokiwa, Kentaro Watanabe, Hiroaki Ohno, Hiroko Tsutsumi, Yoji Hata, Kazuki Izumi, Eiichi Kodama, Masao Matsuoka, Shinya Oishi, Nobutaka Fujii

    BIOORGANIC & MEDICINAL CHEMISTRY 17 (21) 7487-7492 2009年11月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2009.09.015  

    ISSN:0968-0896

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    Bioorganic synthesis of N- and C-terminal end-capped peptides by two simultaneous S-cyanocysteine-mediated cleavages of recombinant proteins is described. This approach is demonstrated in the preparation of anti-HIV fusion inhibitory peptides. (C) 2009 Elsevier Ltd. All rights reserved.

  92. X-ray Crystallographic Study of an HIV-1 Fusion Inhibitor with the gp41 S138A Substitution 査読有り

    Tsuyoshi Watabe, Yukihiro Terakawa, Kentaro Watanabe, Hiroaki Ohno, Hiroaki Nakano, Toru Nakatsu, Hiroaki Kato, Kazuki Izumi, Eiichi Kodama, Masao Matsuoka, Kazuo Kitaura, Shinya Oishi, Nobutaka Fujii

    JOURNAL OF MOLECULAR BIOLOGY 392 (3) 657-665 2009年9月

    出版者・発行元:ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.jmb.2009.07.027  

    ISSN:0022-2836

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    The S138A substitution of fusion inhibitory peptides derived-from the C-terminal heptad repeat (C-HR) of the human immunodeficiency virus type 1 (HIV-1) gp41 leads to enhanced binding affinity to the N-terminal heptad repeat (N-HR). As such, these peptides exhibit highly potent anti-HIV-1 activity. X-ray crystallographic analysis was performed to understand the effect of the substitution on binding affinity. The comparison of the native and S138A crystal structures indicated that the increase in the hydrophobicity of the S138A substitution may aid the stabilization of the N-HR/C-HR complex through additional hydrophobic contacts. Free-energy calculations suggest that the difference between the desolvation free energies of the C-HR-derived peptides with and without the S138A mutation dominates the observed difference in anti-HIV-1 activity. (C) 2009 Elsevier Ltd. All rights reserved.

  93. Design and synthesis of membrane fusion inhibitors against the feline immunodeficiency virus 査読有り

    Shinya Oishi, Yasuyo Kodera, Hiroki Nishikawa, Hirotaka Kamitani, Tsuyoshi Watabe, Hiroaki Ohno, Tadafumi Tochikura, Kazuki Shimane, Eiichi Kodama, Masao Matsuoka, Fuminori Mizukoshi, Hajime Tsujimoto, Nobutaka Fujii

    BIOORGANIC & MEDICINAL CHEMISTRY 17 (14) 4916-4920 2009年7月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2009.06.001  

    ISSN:0968-0896

    eISSN:1464-3391

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    Feline immunodeficiency virus (FIV) is a pathogenic virus that causes an AIDS-like syndrome in the domestic cats. For viral entry and infection, fusion between the virus and the cell membrane is the critical process and this process is mediated by an envelope glycoprotein gp40. We have identified fusion inhibitory peptides from the heptad repeat-2 (HR2) of gp40. Remodeling of the original sequences using alpha-helix-inducible motifs revealed the interactive residues of gp40. Comparative analysis of HR2 peptides derived from four FIV strains demonstrated that the interactive surface of the Shizuoka strain-derived HR2 peptides provides the highest affinity of all the FIV strains examined. (C) 2009 Elsevier Ltd. All rights reserved.

  94. Clinical relevance of substitutions in the connection subdomain and RNase H domain of HIV-1 reverse transcriptase from a cohort of antiretroviral treatment-naive patients 査読有り

    Atsuko Hachiya, Kazuki Shimane, Stefan G. Sarafianos, Eiichi N. Kodama, Yasuko Sakagami, Fujie Negishi, Hirokazu Koizumi, Hiroyuki Gatanaga, Masao Matsuoka, Masafumi Takiguchi, Shinichi Oka

    ANTIVIRAL RESEARCH 82 (3) 115-121 2009年6月

    出版者・発行元:ELSEVIER SCIENCE BV

    DOI: 10.1016/j.antiviral.2009.02.189  

    ISSN:0166-3542

    eISSN:1872-9096

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    Some mutations in the connection subdomain of the polymerase domain and in the RNase H domain of HIV-1 reverse transcriptase (RT) have been shown to contribute to resistance to RT inhibitors. However, the clinical relevance of such mutations is not well understood. To address this point we determined the prevalence of such mutations in a cohort of antiretroviral treatment-naive patients (n=123) and assessed whether these substitutions are associated with drug resistance in vitro and in vivo. We report here significant differences in the prevalence of substitutions among subtype B, and non-subtype B HIV isolates. Specifically, the E312Q G333E, G335D, V365I, A371V and A376S substitutions were present in 2-6% of subtype B, whereas the G335D and A371V substitutions were commonly observed in 69% and 75% of non-B HIV-1 isolates. We observed a significant decline in the viral loads of patients that were infected with HIV-1 carrying these substitutions and were subsequently treated with triple drug regimens, even in the case where zidovudine (AZT) was included in such regimens. We show here that, generally, such single substitutions at the connection subdomain or RNase H domain have no influence on drug susceptibility in vitro by themselves. Instead, they generally enhance AZT resistance in the presence of excision-enhancing mutations (EEMs, also known as thymidine analogue-associated mutations, TAMs). However, N348I, A376S and Q509L did confer varying amounts of nevirapine resistance by themselves, even in the absence of EEMs. Our studies indicate that several connection subdomain and RNase H domain substitutions typically act as pre-therapy polymorphisms. (C) 2009 Elsevier B.V. All rights reserved.

  95. Electrostatically constrained alpha-helical peptide inhibits replication of HIV-1 resistant to enfuvirtide 査読有り

    Hiroki Nishikawa, Shota Nakamura, Efichi Kodama, Saori Ito, Keiko Kajiwara, Kazuki Izumi, Yasuko Sakagami, Shinya Oishi, Tadayasu Ohkubo, Yuji Kobayashi, Akira Otaka, Nobutaka Fujii, Masao Matsuoka

    INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 41 (4) 891-899 2009年4月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.biocel.2008.08.039  

    ISSN:1357-2725

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    alpha-Helical pepticles, such as T-20 (enfuvirtide) and C34, derived from the gp41 carboxyl-terminal heptad repeat (C-HR) of HIV-1, inhibit membrane fusion of HIV-1 and the target cells. Although T-20 effectively suppresses the replication of multi-drug resistant HIV variants both in vitro and in vivo, prolonged therapy with T-20 induces emergence of T-20 resistant variants. In order to suppress the emergence of such resistant variants, we introduced charged and hydrophilic amino acids, glutamic acid (E) and lysine (K), at the solvent accessible site of C34. In particular, the modified peptide, SC34EK, demonstrates remarkably potent inhibition of membrane fusion by the resistant HIV-1 variants as well as wild-type viruses. The activity was specific to HIV-1 and little influenced by serum components. We found a strong correlation between the anti-HIV-1 activities of these pepticles and the thermostabilities of the 6-helix bundles that are formed with these peptides. We also obtained the crystal structure of SC34EK in complex with a 36 amino acid sequence (N36) comprising the amino-terminal heptad repeat of HIV-1. The EK substitutions in the sequence of SC34EK were directed toward the solvent and generated an electrostatic potential, which may result in enhanced alpha-helicity of the peptide inhibitor. The 6-helix bundle complex of SC34EK with N36 appears to be structurally similar to that of C34 and N36. Our approach to enhancing alpha-helicity of the peptide inhibitor may enable future design of highly effective and specific HIV-1 inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.

  96. Synonymous mutations in stem-loop III of Rev responsive elements enhance HIV-1 replication impaired by primary mutations for resistance to enfuvirtide 査読有り

    Mariko Ueno, Eiichi N. Kodama, Kazuya Shimura, Yasuteru Sakurai, Keiko Kajiwara, Yasuko Sakagami, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka

    ANTIVIRAL RESEARCH 82 (1) 67-72 2009年4月

    出版者・発行元:ELSEVIER SCIENCE BV

    DOI: 10.1016/j.antiviral.2009.02.002  

    ISSN:0166-3542

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    Primary mutations in HIV-1 that are directly involved in the resistance to enfuvirtide have been well documented. However, secondary mutations that are associated with primary mutations and contribute little to the resistance still remain to be elucidated. This study reveals that synonymous mutations at gp41 Q41 (CAG to CAA) or L44 (UUG to CUG) act as secondary mutations. Complementary mutations in the nucleotide level are located in the Rev responsive element (RRE) of the HIV-1 RNA-genome and maintain the replication kinetics of HIV-1 through increasing the structural stability of stem-loop III in the RRE. Therefore, synonymous mutations in the gp41/RRE sequence improve the viral replication impaired by the primary mutations and play a key role as secondary (complementary) mutations. (C) 2009 Elsevier B.V. All rights reserved.

  97. Elvitegravir: a new HIV integrase inhibitor. 査読有り

    Shimura Kazuya, Kodama Eiichi N

    Antivir Chem Chemother 20 (2) 79-85 2009年4月

    DOI: 10.3851/IMP1397  

  98. SC29EK, a Peptide Fusion Inhibitor with Enhanced alpha-Helicity, Inhibits Replication of Human Immunodeficiency Virus Type 1 Mutants Resistant to Enfuvirtide 査読有り

    Takeshi Naito, Kazuki Izumi, Eiichi Kodama, Yasuko Sakagami, Keiko Kajiwara, Hiroki Nishikawa, Kentaro Watanabe, Stefan G. Sarafianos, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 53 (3) 1013-1018 2009年3月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/AAC.01211-08  

    ISSN:0066-4804

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    Peptides derived from the alpha-helical domains of human immunodeficiency virus (HIV) type 1 (HIV-1) gp41 inhibit HIV-1 fusion to the cell membrane. Enfuvirtide (T-20) is a peptide-based drug that targets the step of HIV fusion, and as such, it effectively suppresses the replication of HIV-1 strains that are either wild type or resistant to multiple reverse transcriptase and/or protease inhibitors. However, HIV-1 variants with T-20 resistance have emerged; therefore, the development of new and potent inhibitors is urgently needed. We have developed a novel HIV fusion inhibitor, SC34EK, which is a gp41-derived 34-amino-acid peptide with glutamate (E) and lysine (K) substitutions on its solvent-accessible site that stabilize its alpha-helicity. Importantly, SC34EK effectively inhibits the replication of T-20-resistant HIV-1 strains as well as wild-type HIV-1. In this report, we introduce SC29EK, a 29-amino-acid peptide that is a shorter variant of SC34EK. SC29EK blocked the replication of T-20-resistant HIV-1 strains and maintained antiviral activity even in the presence of high serum concentrations (up to 50%). Circular dichroism analysis revealed that the alpha-helicity of SC29EK was well maintained, while that of the parental peptide, C29, which showed moderate and reduced inhibition of wild-type and T-20-resistant HIV-1 strains, was lower. Our results show that the alpha-helicity in a peptide-based fusion inhibitor is a key factor for activity and enables the design of short peptide inhibitors with improved pharmacological properties.

  99. Design of Peptide-based Inhibitors for Human Immunodeficiency Virus Type 1 Strains Resistant to T-20 査読有り

    Kazuki Izumi, Eiichi Kodama, Kazuya Shimura, Yasuko Sakagami, Kentaro Watanabe, Saori Ito, Tsuyoshi Watabe, Yukihiro Terakawa, Hiroki Nishikawa, Stefan G. Sarafianos, Kazuo Kitaura, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka

    JOURNAL OF BIOLOGICAL CHEMISTRY 284 (8) 4914-4920 2009年2月

    出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI: 10.1074/jbc.M807169200  

    ISSN:0021-9258

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    Enfuvirtide (T-20) is a fusion inhibitor that suppresses replication of human immunodeficiency virus (HIV) variants with multi-drug resistance to reverse transcriptase and protease inhibitors. It is a peptide derived from the C-terminal heptad repeat (C-HR) of HIV-1 gp41, and it prevents interactions between the C-HR and the N-terminal HR (N-HR) of gp41, thus interfering with conformational changes that are required for viral fusion. However, prolonged therapies with T-20 result in the emergence of T-20-resistant strains that contain primary mutations such as N43D in the N-HR of gp41 (where T-20 and C-HR bind) that help the virus escape at a fitness cost. Such variants often go on to acquire a secondary mutation, S138A, in the C-HR of gp41 region that corresponds to the sequence of T-20. We demonstrate here that the role of S138A is to compensate for the impaired fusion kinetics of HIV-1s carrying primary mutations that abrogate binding of T-20. To preempt this escape strategy, we designed a modified T-20 variant containing the S138A substitution and showed that it is a potent inhibitor of both T-20-sensitive and T-20-resistant viruses. Circular dichroism analysis revealed that the S138A provided increased stability of the 6-helix bundle. We validated our approach on another fusion inhibitor, C34. In this case, we designed a variant of C34 with the secondary escape mutation N126K and showed that it can effectively inhibit replication of C34-resistant HIV-1. These results prove that it is possible to design improved peptide-based fusion inhibitors that are efficient against a major mechanism of drug resistance.

  100. Development of a novel fusion inhibitor against T-20-resistant HIV-1. 査読有り

    Oishi S, Ito S, Nishikawa H, Tanaka M, Ohno H, Otaka A, Izumi K, Kodama E, Matsuoka M, Fujii N

    Advances in experimental medicine and biology 611 389-391 2009年

    DOI: 10.1007/978-0-387-73657-0_170  

    ISSN:0065-2598

  101. Peptide bond mimicry by (E)-alkene and (Z)-fluoroalkene peptide isosteres: synthesis and bioevaluation of alpha-helical anti-HIV peptide analogues 査読有り

    Shinya Oishi, Hirotaka Kamitani, Yasuyo Kodera, Kentaro Watanabe, Kazuya Kobayashi, Tetsuo Narumi, Kenji Tomita, Hiroaki Ohno, Takeshi Naito, Eiichi Kodama, Masao Matsuoka, Nobutaka Fujii

    ORGANIC & BIOMOLECULAR CHEMISTRY 7 (14) 2872-2877 2009年

    出版者・発行元:ROYAL SOC CHEMISTRY

    DOI: 10.1039/b907983a  

    ISSN:1477-0520

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    The alpha-helix structures of the anti-HIV fusion inhibitory peptides are stabilized by the amino acid sequence and by intrachain hydrogen bonds. The study of peptide analogues using (E)-alkene and (Z)-fluoroalkene dipeptide isosteres demonstrated the substantial, yet position-dependent, contribution of hydrogen bonds to the alpha-helix stability and anti-HIV bioactivity.

  102. Novel screening systems for HIV-1 fusion mediated by two extra-virion heptad repeats of gp41 査読有り

    Hiroki Nishikawa, Eiichi Kodama, Ayako Sakakibara, Ayako Fukudome, Kazuki Izumi, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka

    ANTIVIRAL RESEARCH 80 (1) 71-76 2008年10月

    出版者・発行元:ELSEVIER SCIENCE BV

    DOI: 10.1016/j.antiviral.2008.05.006  

    ISSN:0166-3542

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    Entry of human immunodeficiency virus type 1 (HIV-1) into target cells is mediated by its envelope protein gp41 through membrane fusion. Interaction of two extra-virion heptad repeats (HRs) in the gp41 plays a pivotal role in the fusion, and its inhibitor, enfuvirtide (T-20), blocks HIV-1 entry. To identify agents that block HIV-1 fusion, two screening methods based on detection and quantification by the enzyme-linked immunosorbent assay (ELISA) principle have been established. One method uses an alkaline phosphatase (ALP)-conjugated antibody (Ab-ELISA) and the other uses an ALP-fused HR (F-ELISA) to detect and quantify the interaction of the two HRs. The F-ELISA was more simple and rapid, since no ALP-conjugated antibody reaction was required. Both ELISAs detected all the fusion inhibitors tested except for T-20. Interaction of the two HRs was observed in both ELISAs, even in the presence of 10% dimethyl sulfoxide. Ab-ELISA performed best in a pH ranging from 6 to 8, while F-ELISA performed best at a pH ranging from 7 to 8. These results indicate that both established ELISAs are suitable for the identification of HIV-1 fusion inhibitors. (C) 2008 Elsevier B.V. All rights reserved.

  103. Identification of minimal sequence for HIV-1 fusion inhibitors 査読有り

    Hiroki Nishikawa, Shinya Oishi, Mizuno Fujita, Kentaro Watanabe, Rei Tokiwa, Hiroaki Ohno, Eiichi Kodama, Kazuki Izumi, Keiko Kajiwara, Takeshi Naitoh, Masao Matsuoka, Akira Otaka, Nobutaka Fujii

    BIOORGANIC & MEDICINAL CHEMISTRY 16 (20) 9184-9187 2008年10月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2008.09.018  

    ISSN:0968-0896

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    Emergence of multi-drug resistant HIV-1 is a serious problem for AIDS treatment. Recently, the virus-cell membrane fusion process has been identified as a promising target for the development of novel drugs against these resistant variants. In this study, we identified a 29-residue peptide fusion inhibitor, SC29EK, which shows activity comparable to the previously reported inhibitor SC35EK. Some residues in SC29EK not required for interaction with virus gp41 heptad repeat 1 (HR1) were replaced with a non-proteinogenic amino acid, 2-aminoisobutyric acid (Aib), to stabilize the alpha-helix structure and to provide resistance to peptidases. (C) 2008 Elsevier Ltd. All rights reserved.

  104. Identification of novel non-peptide CXCR4 antagonists by ligand-based design approach 査読有り

    Satoshi Ueda, Manabu Kato, Shinsuke Inuki, Hiroaki Ohno, Barry Evans, Zi-xuan Wang, Stephen C. Peiper, Kazuki Izumi, Eiichi Kodama, Masao Matsuoka, Hideko Nagasawa, Shinya Oishi, Nobutaka Fujii

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 18 (14) 4124-4129 2008年7月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmcl.2008.05.092  

    ISSN:0960-894X

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    The design and synthesis of novel non-peptide CXCR4 antagonists is described. The peptide backbone of highly potent cyclic peptide-based CXCR4 antagonists was entirely replaced by an indole framework, which was expected to reproduce the disposition of the key pharmacophores consistent with those of potential bioactive conformations of the original peptides. A structure-activity relationship study on a series of modified indoles identified novel small-molecule antagonists having three pharmacophore functional groups through the appropriate linkers. (c) 2008 Elsevier Ltd. All rights reserved.

  105. Novel inhibition mechanism and potent activity of trans location-deficient reverse transcriptase inhibitors 査読有り

    Michailidis Lefteris, Marchand Bruno, Kodama Ei-Ichi, Fopoussi Amelie, Olga Mafotsing, Sawani Ali, Ryan Emilie, Eisele Nicholas, Matsuoka Masao, Ashida Noriyuki, Nagy Eva, Parniak Michael, Mitsuya Hiroaki, Sarafianos Stefan

    INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES 12 S24-S25 2008年6月

    DOI: 10.1016/S1201-9712(08)60058-2  

    ISSN:1201-9712

  106. Synthesis and application of fluorescein- and biotin-labeled molecular probes for the chemokine receptor CXCR4 査読有り

    Shinya Oishi, Ryo Masuda, Barry Evans, Satoshi Ueda, Yukiko Goto, Hiroaki Ohno, Akira Hirasawa, Gozoh Tsujimoto, Zixuan Wang, Stephen C. Peiper, Takeshi Naito, Eiichi Kodama, Masao Matsuoka, Nobutaka Fujii

    CHEMBIOCHEM 9 (7) 1154-1158 2008年5月

    出版者・発行元:WILEY-V C H VERLAG GMBH

    DOI: 10.1002/cbic.200700761  

    ISSN:1439-4227

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    The design, synthesis, and bioevaluation of fluorescence- and biotin-labeled CXCR4 antagonists are described The modification Of D-Lys8 at an e-amino group in the peptide antagonist Ac-TZ14071 derived from polyphemusin II hod no significant influence on the potent binding of the peptide to the CXCR4 receptor. The application of the labeled peptides in flow cytometry and confocal microscopy studies demonstrated the selectivity of their binding to the CXCR4 receptor, but not to CXCR7, which was recently, reported to be another receptor for stromal cell-derived factor 1 (SDF-1)/CXCL12.

  107. Amino acid mutation N348I in the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase confers multiclass resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors 査読有り

    Atsuko Hachiya, Eiichi N. Kodama, Stefan G. Sarafianos, Matthew M. Schuckmann, Yasuko Sakagami, Masao Matsuoka, Masafumi Takiguchi, Hiroyuki Gatanaga, Shinichi Oka

    JOURNAL OF VIROLOGY 82 (7) 3261-3270 2008年4月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/JVI.01154-07  

    ISSN:0022-538X

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    We identified clinical isolates with phenotypic resistance to nevirapine (NVP) in. the absence of known nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations. This resistance is caused by N348I, a mutation at the connection subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Virologic analysis showed that N348I conferred multiclass resistance to NNRTIs (NVP and delavirdine) and to nucleoside reverse transcriptase inhibitors (zidovudine [AZT] and didanosine [ddI]). N348I impaired HIV-1 replication in a cell-type-dependent manner. Acquisition of N348I was frequently observed in AZT- and/or ddI-containing therapy (12.5%; n = 48; P &lt; 0.0001) and was accompanied with thymidine analogue-associated mutations, e.g., T215Y (n = 5/6) and the lamivudine resistance mutation M184V (n = 1/6) in a Japanese cohort. Molecular modeling analysis shows that residue 348 is proximal to the NNRTI-binding pocket and to a flexible hinge region at the base of the p66 thumb that may be affected by the N348I mutation. Our results further highlight the role of connection subdomain residues in drug resistance.

  108. Dual-reporter phenotypic assay for human immunodeficiency viruses 査読有り

    Keiko Kajiwara, Eiichi Kodama, Yasuko Sakagami, Takeshi Naito, Masao Matsuoka

    JOURNAL OF CLINICAL MICROBIOLOGY 46 (2) 792-795 2008年2月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/JCM.01470-07  

    ISSN:0095-1137

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    We have established a novel human immunodeficiency virus (HIV) tandem-reporter assay using HIV receptor-transduced NP-2 cells with long terminal repeat-controlled beta-galactosidase, inserted internal ribosome entry site, and secretary alkaline phosphatase genes. This assay allows users to detect replication of clinical isolates, indicating its useful application as an HIV phenotypic assay.

  109. Design of a novel HIV-1 fusion inhibitor that displays a minimal interface for binding affinity 査読有り

    Shinya Oishi, Saori Ito, Hiroki Nishikawa, Kentaro Watanabe, Michinori Tanaka, Hiroaki Ohno, Kazuki Izumi, Yasuko Sakagami, Eiichi Kodama, Masao Matsuoka, Nobutaka Fujii

    JOURNAL OF MEDICINAL CHEMISTRY 51 (3) 388-391 2008年2月

    出版者・発行元:AMER CHEMICAL SOC

    DOI: 10.1021/jm701109d  

    ISSN:0022-2623

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    Reported herein are the design, biological activities, and biophysical properties of a novel HIV-1 membrane fusion inhibitor. alpha-Helix-inducible X-EE-YX-KK motifs were applied to design an enfuvirtide analogue 2 that exhibited highly potent anti-HIV activity against wild-type HIV-1, enfuvirtide-resistant HIV-1 strains, and an HIV-2 strain in vitro. Indispensable residues for bioactivity of enfuvirtide, including the residues interacting with the N-terminal heptad repeat and the C-terminal hydrophobic residues, were identified.

  110. Broad Antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137) 査読有り

    Kazuya Shimura, Eiichi Kodama, Yasuko Sakagami, Yuji Matsuzaki, Wataru Watanabe, Kazunobu Yamataka, Yasuo Watanabe, Yoshitsugu Ohata, Satoki Doi, Motohide Sato, Mitsuki Kano, Satoru Ikeda, Masao Matsuoka

    JOURNAL OF VIROLOGY 82 (2) 764-774 2008年1月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/JVI.01534-07  

    ISSN:0022-538X

    eISSN:1098-5514

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    Integrase (IN), an essential enzyme of human immunodeficiency virus (HIV), is an attractive antiretroviral drug target. The antiviral activity and resistance profile in vitro of a novel IN inhibitor, elvitegravir (EVG) (also known as JTK-303/GS-9137), currently being developed for the treatment of HIV-1 infection are described. EVG blocked the integration of HIV-1 cDNA through the inhibition of DNA strand transfer. EVG inhibited the replication of HIV-1, including various subtypes and multiple-drug-resistant clinical isolates, and HIV-2 strains with a 50% effective concentration in the subnanomolar to nanomolar range. EVG-resistant variants were selected in two independent inductions, and a total of 8 amino acid substitutions in the catalytic core domain of IN were observed. Among the observed IN mutations, T661 and E92Q substitutions mainly contributed to EVG resistance. These two primary resistance mutations are located in the active site, and other secondary mutations identified are proximal to these primary mutations. The EVG-selected IN mutations, some of which represent novel IN inhibitor resistance mutations, conferred reduced susceptibility to other IN inhibitors, suggesting that a common mechanism is involved in resistance and potential cross-resistance. The replication capacity of EVG-resistant variants was significantly reduced relative to both wild-type virus and other IN inhibitor-resistant variants selected by L-870,810. EVG and L-870,810 both inhibited the replication of murine leukemia virus and simian immunodeficiency virus, suggesting that IN inhibitors bind to a conformationally conserved region of various retroviral IN enzymes and are an ideal drug for a range of retroviral infections.

  111. Heptad repeat-derived peptides block protease-mediated direct entry from the cell surface of severe acute respiratory syndrome coronavirus but not entry via the endosomal pathway 査読有り

    Makoto Ujike, Hiroki Nishikawa, Akira Otaka, Naoki Yamamoto, Norio Yamamoto, Masao Matsuoka, Eiichi Kodama, Nobutaka Fujii, Fumihiro Taguchi

    JOURNAL OF VIROLOGY 82 (1) 588-592 2008年1月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/JVI.01697-07  

    ISSN:0022-538X

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    The peptides derived from the heptad repeat (HRP) of severe acute respiratory syndrome coronavirus (SCoV) spike protein (sHRPs) are known to inhibit SCoV infection, yet their efficacies are fairly low. Recently our research showed that some proteases facilitated SCoVs direct entry from the cell surface, resulting in a more efficient infection than the previously known infection via endosomal entry. To compare the inhibitory effect of the sHRP in each pathway, we selected two sHRPs, which showed a strong inhibitory effect on the interaction of two heptad repeats in a rapid and virus-free in vitro assay system. We found that they efficiently inhibited SCoV infection of the protease-mediated cell surface pathway but had little effect on the endosomal pathway. This finding suggests that sHRPs may effectively prevent infection in the lungs, where SCoV infection could be enhanced by proteases produced in this organ. This is the first observation that HRP exhibits different effects on virus that takes the endosomal pathway and virus that enters directly from the cell surface.

  112. Binding modes of two novel non-nucleoside reverse transcriptase inhibitors, YM-215389 and YM-228855, to HIV type-1 reverse transcriptase 査読有り

    Eiichi Kodoma, Masaya Orita, Naoyuki Masuda, Osamu Yamamoto, Masahiro Fujii, Tetsuro Ohgami, Shunji Kageyama, Mitsuaki Ohta, Toshifumi Hatta, Hiroshi Inoue, Hiroshi Suzuki, Kenji Sudo, Yasuaki Shimizu, Masao Matsuoka

    Antiviral Chemistry and Chemotherapy 19 (3) 133-141 2008年

    ISSN:0956-3202

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    Background: YM-215389 and YM-228855 are thiazolidenebenzenesulfonamide (TBS) derivatives and novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) that inhibit not only wild-type, but also the K103N-and Y181C-substituted reverse transcriptase (RT) of HIV type-1 (HIV-1). Methods: To characterize the binding modes of the TBS derivatives in detail, the anti-HIV-1 activities of YM-215389 and YM-228855 against various NNRTI-resistant clones were examined. Docking studies with HIV-1 RT were also performed. Results: YM-215389, which effectively inhibits various NNRTI-resistant clones, interacted with L100, K103, V106 and Y318 through the benzene ring and with E138, V179, Y181, Y188 and W229 through the thiazole ring. A single amino acid substitution confers only moderate resistance to YM-215389 indeed, four amino acid substitutions (V106L,V1081, E138K and L214F) were necessary for high-level resistance. Although the activity of YM-228855, a derivative of YM-215389 that has two bulky and rigid cyano-moieties on the benzene ring, was 10x more potent against HIV-1 than YM-215389, its anti-HIV-1 activity was readily reduced with single substitutions as with Y181I and K103N. Conclusions: These results provide structural information for optimizing the TBS derivatives in an attempt to construct ideal NNRTIs that maintain anti-HIV-1 activity to various HIV-1 variants. © 2008 International Medical Press.

  113. 2 '-deoxy-4 '-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants 査読有り

    Atsushi Kawamoto, Eiichi Kodama, Stefan G. Sarafianos, Yasuko Sakagami, Satoru Kohgo, Kenji Kitano, Noriyuki Ashida, Yuko Iwai, Hiroyuki Hayakawa, Hirotomo Nakata, Hiroaki Mitsuya, Eddy Arnold, Masao Matsuoka

    INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 40 (11) 2410-2420 2008年

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.biocel.2008.04.007  

    ISSN:1357-2725

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    One of the formidable challenges in therapy of infections by human immunodeficiency virus (HIV) is the emergence of drug-resistant variants that attenuate the efficacy of highly active antiretroviral therapy (HAART). We have recently introduced 4'-ethynylnucleoside analogs as nucleoside reverse transcriptase inhibitors (NRTIs) that could be developed as therapeutics for treatment of HIV infections. In this study, we present 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (EFdA), a second generation 4'-ethynyl inhibitor that exerted highly potent activity against wild-type HIV-1 (EC50 similar to 0.07 nM). EFdA retains potency toward many HIV-1 resistant strains, including the multi-drug resistant clone HIV-1(A62V/V751/F77L/F116Y/Q151M). The selectivity index of EFdA (cytotoxicity/inhibitory activity) is more favorable than all approved NRTIs used in HIV therapy. Furthermore, EFdA efficiently inhibited clinical isolates from patients heavily treated with multiple anti-HIV-1 drugs. EFdA appears to be primarily phosphorylated by the cellular 2'-deoxycytidine kinase (dCK) because: (a) the antiviral activity of EFdA was reduced by the addition of dC, which competes nucleosides phosphorylated by the dCK pathway, (b) the antiviral activity of EFdA was significantly reduced in dCK-deficient HT-1080/Ara-C-r cells, but restored after dCK transduction. Further, unlike other dA analogs, EFdA is completely resistant to degradation by adenosine deaminase. Moderate decrease in susceptibility to EFdA is conferred by a combination of three RT mutations (I142V, T165R, and M184V) that result in a significant decrease of viral fitness. Molecular modeling analysis suggests that the M184V/I substitutions may reduce anti-HIV activity of EFdA through steric hindrance between its 4'-ethynyl moiety and the V/I184 beta-branched side chains. The present data suggest that EFdA, is a promising candidate for developing as a therapeutic agent for the treatment of individuals harboring multi-drug resistant HIV variants. (C) 2008 Elsevier Ltd. All rights reserved.

  114. Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA Polymerases of 4 '-ethynyl-2-fluoro-2 '-deoxyadenosine 査読有り

    Hirotorao Nakata, Masayuki Amano, Yasuhiro Koh, Eiichi Kodama, Guangwei Yang, Christopher M. Bailey, Satoru Kohgo, Hiroyuki Hayakawa, Masao Matsuoka, Karen S. Anderson, Yung-Chi Cheng, Hiroaki Mitsuya

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 51 (8) 2701-2708 2007年8月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/AAC.00277-07  

    ISSN:0066-4804

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    We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fiuoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 mu M [H-3]EFdA or [H-3]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 mu M [(3)HEFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [H-3]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were similar to 17 and similar to 3 h, respectively. When MT-4 cells were cultured with 0.01 mu M EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3),and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 mu M AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were &gt;100 mu M, &gt;100 mu M, and 10 mu M, respectively, while those of ddA-TP were &gt;100 mu M, 0.2 mu M, and 0.2 mu M, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.

  115. 2 '-deoxy-4 '-C-ethynyl-2-fluoroadenosine: A nucleoside reverse transcriptase inhibitor with highly potent activity against wide spectrum of hiv-1 strains, favorable toxic profiles, and stability in plasma 査読有り

    Hiroshi Ohrui, Satoru Kohgo, Hiroyuki Hayakawa, Eiichi Kodama, Masao Matsuoka, Tomohiro Nakata, Hiroaki Mitsuya

    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 26 (10-12) 1543-1546 2007年

    出版者・発行元:TAYLOR & FRANCIS INC

    DOI: 10.1080/15257770701545218  

    ISSN:1525-7770

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    Working hypotheses to solve the critical problems of the existing highly active anti-retroviral therapy were proposed. The study based on the hypotheses proved the validity of the hypotheses and resulted in the development of 2'deoxy-4'C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, with highly potent activity against all HIV-1, very favorable toxic profiles, and stability in plasma. The nucleoside will prevent or delay the emergence of drug-resistant HIV-1 variants and be an ideal therapeutic agent for both HIV-1 and HBV infections.

  116. A high collusion-resistant approach to distributed privacy-preserving data mining. 査読有り

    Shintaro Urabe, Jiahong Wang, Eiichiro Kodama, Toyoo Takata

    Proceedings of the IASTED International Conference on Parallel and Distributed Computing and Networks, as part of the 25th IASTED International Multi-Conference on Applied Informatics, February 13-15 2007, Innsbruck, Austria 307-312 2007年

    出版者・発行元:IASTED/ACTA Press

  117. Structural basis for the interaction of CCR5 with a small molecule, functionally selective CCRS agonist 査読有り

    Yuji Saita, Eiichi Kodama, Masaya Orita, Mitsuhiro Kondo, Takahiro Miyazaki, Kenji Sudo, Keiko Kajiwara, Masao Matsuoka, Yasuaki Shimizu

    JOURNAL OF IMMUNOLOGY 177 (5) 3116-3122 2006年9月

    出版者・発行元:AMER ASSOC IMMUNOLOGISTS

    ISSN:0022-1767

    eISSN:1550-6606

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    The chemokine receptor CCR5 is an attractive target for HIV-1 drug development, as individuals whose cells lack surface CCR5 expression are highly resistant to HIV-1 infection. CCR5 ligands, such as CCL5/RANTES, effectively inhibit HIV-1 infection by competing for binding opportunities to the CCR5 and inducing its internalization. However, the inherent proinflammatory activity of the chemotactic response of CCR5 ligands has limited their clinical use. In this study, we found that a novel small molecule, functionally selective CCR5 agonist, 2,2-dichloro-l-(triphenylphosphonio)vinyl formamide perchlorate (YM-370749), down-modulates CCR5 from the cell surface without inducing a chemotactic response and inhibits HIV-1 replication. In molecular docking studies of YM-370749 and a three-dimensional model of CCR5 based on the rhodopsin crystal structure as well as binding and functional studies using various CCR5 mutants, the amino acid residues necessary for interaction with YM-370749 were marked. These results provide a structural basis for understanding the activation mechanism of CCR5 and for designing functionally selective agonists as a novel class of anti-HIV-1 agents.

  118. P-39 2'-DEXY-4'-C-ETHYNYL-2-FLUOROADENOSINE, A NRTI THAT COULD BE AN IDEAL DRUG FOR BOTH HIV-AND HBV-INFECTIONS

    Ohrui Hiroshi, Kohgo Satoru, Hayakawa Hiroyuki, Kodama Eiichi, Matsuoka Masao, Mitsuya Hiroaki

    International Symposium on the Chemistry of Natural Products 2006 "P-39" 2006年7月23日

    出版者・発行元:天然有機化合物討論会

    DOI: 10.24496/intnaturalprod.2006.0__P-39_  

  119. 2'-Deoxy-4'-C-ethynyl-2-fluoroadenosine: a nucleoside reverse transcriptase inhibitor with highly potent activity against all HIV-1 strains, favorable toxic profiles and stability in plasma. 査読有り

    Ohrui Hiroshi, Kohgo Satoru, Hayakawa Hiroyuki, Kodama Eiichi, Matsuoka Masao, Nakata Tomohiro, Mitsuya Hiroyuki

    Nucleic Acids Symp Ser (Oxf) (50) 1-2 2006年4月

    DOI: 10.1093/nass/nrl001  

  120. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics 招待有り 査読有り

    M Sato, T Motomura, H Aramaki, T Matsuda, M Yamashita, Y Ito, H Kawakami, Y Matsuzaki, W Watanabe, K Yamataka, S Ikeda, E Kodama, M Matsuoka, H Shinkai

    JOURNAL OF MEDICINAL CHEMISTRY 49 (5) 1506-1508 2006年3月

    出版者・発行元:AMER CHEMICAL SOC

    DOI: 10.1021/jm0600139  

    ISSN:0022-2623

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    The viral enzyme integrase is essential for the replication of human immunodeficiency virus type 1 (HIV-1) and represents a remaining target for antiretroviral drugs. Here, we describe the modification of a quinolone antibiotic to produce the novel integrase inhibitor JTK-303 (GS 9137) that blocks strand transfer by the viral enzyme. It shares the core structure of quinolone antibiotics, exhibits an IC50 of 7.2 nM in the strand transfer assay, and shows an EC50 of 0.9 nM in an acute HIV-1 infection assay.

  121. Creation of low toxic reverse-transcriptase inhibitory nucleosides that prevent the emergence of drug-resistant HIV variants 査読有り

    Hiroshi Ohrui, Hiroyuki Hayakawa, Satoru Kohgo, Masao Matsuoka, Eiichi Kodama, Hiroaki Mitsuya

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry 64 (7) 716-723 2006年

    出版者・発行元:Society of Synthetic Organic Chemistry

    DOI: 10.5059/yukigoseikyokaishi.64.716  

    ISSN:0037-9980

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    Although the Highly Active Anti-Retroviral Therapy (HAART) has dramatically improved the quality of life and the prognosis of patients infected with HIV, development of more active and less toxic drugs that prevent the emergence of drug-resistant HIV variants is strongly required, due to the emergence of new drug-resistant HIV variants, need of taking a large quantity of drugs, and side effects of the drugs. The principal author has proposed a concept to prevent the emergence of the HIV variants resistant to reverse-transcriptase (RT) inhibitory nucleosides. Based on the concept, 4′ -C-substituted-2′-deoxynucleoside (4′Sd-N)* 1 was designed as the anti-HIV nucleoside that could prevent the emergence of resistant HIV variants. Various kinds of 4′Sd-N were synthesized and evaluated for biological activity. 2′-Deoxy-4′-C-ethynyl-2-fluoroadenosine (4′Ed-2FA) which is stable to adenosine deaminase turned out to be highly active against all HIV-1 including multi-drug resistant variants and very lowly toxic, and so far no HIV-1 variants resistant to it emerged. These results suggest that once-daily-dosing schedule of 4′Ed-2FA is possible presumably with few side effects and warrant that 4′Ed-2FA be further developed as a potential therapeutic for HIV-1 infection.

  122. A novel colorimetric assay for CXCR4 and CCR5 tropic human immunodeficiency viruses 査読有り

    Keiko Kajiwara, Eiichi Kodama, Masao Matsuoka

    Antiviral Chemistry and Chemotherapy 17 (4) 215-223 2006年

    出版者・発行元:International Medical Press Ltd

    DOI: 10.1177/095632020601700405  

    ISSN:0956-3202

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    The majority of HIV isolated from infected patients uses CCR5 as a coreceptor (R5-HIV). Although R5-HIV fails to replicate efficiently in human transformed T-cell lines, HIV using CXCR4 (X4-HIV) can replicate well in such cell lines. Therefore, most of screening systems using the T-cell lines detect only X4-HIV replication. Here we report a new assay to monitor the replication of R5- as well as X4-HIV. An MTT assay using CD4-, CXCR4-, and CCR5-transduced human glioma NP-2 cells (NCK45 cells) was established and then compared with the representative assays including multinuclear activation of a galactosidase indicator assay (MAGI assay). The antiviral activities of not only an adsorption inhibitor and reverse transcriptase inhibitors but also a Tat antagonist in the NCK45 cells, were comparable to those obtained from the MTT assay using MT-4 cells or the MAGI assay. However, the activity of protease inhibitors (PIs) was underestimated, even though expressions of major multidrug resistant genes involved in efflux of PIs were comparable in MT-2, NP-2, and NCK45 cells. After cultivation of more than 6 months, NCK45 cells remained susceptible to HIV infection since NCK45 cells consistently expressed CD4, CXCR4, and CCR5. On the other hand, MAGI cells lost the CD4 expression during culture. Thus, this assay system can stably detect the replication of both X4- and R5-HIV, indicating that it should be useful for the evaluation of HIV replication and drug susceptibility. ©2006 International Medical Press.

  123. A Scalable Sequential Pattern Mining Algorithm. 査読有り

    Jiahong Wang, Yoshiaki Asanuma, Eiichiro Kodama, Toyoo Takata

    2006 IEEE/ACS International Conference on Computer Systems and Applications (AICCSA 2006), March 8-11, Dubai/Sharjah, UAE 437-444 2006年

    出版者・発行元:IEEE Computer Society

    DOI: 10.1109/AICCSA.2006.205128  

  124. Halogenated thymidine analogues restore the expression of silenced genes without demethylation 査読有り

    J Fan, E Kodama, Y Koh, N Nakao, M Matsuoka

    CANCER RESEARCH 65 (15) 6927-6933 2005年8月

    出版者・発行元:AMER ASSOC CANCER RESEARCH

    DOI: 10.1158/0008-5472.CAN-04-3495  

    ISSN:0008-5472

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    Transcriptional silencing of tumor suppressor genes by aberrant DNA methylation is a characteristic frequently observed in cancer cells. Therefore, reversing this process is a therapeutic target against cancer. In this study, we established a screening system for silencing inhibitors with cell lines transfected by a retroviral vector containing a luciferase gene. More than 100 nucleosides were tested for antisilencing activity with a selected clone in which the silenced expression of luciferase could be recovered by 5-aza-2 '-deoxycytidine. A group of halogenated thymidine analogues was found to reactivate transcription of not only the reporter retrovirus vector but also endogenous glutathione-S-transferase 1 gene, without influence to DNA hypermethylation. Gel mobility shift assay showed that 5-bromo-2 '-deoxyuridine (BrdUrd) or 5-iodo-2 '-deoxyuridine incorporation did not affect the binding of the methyl-CpG binding protein motif to methylated DNA. Finally, in the retroviral promoter, BrdUrd treatment increased the acetylated histone H3 level and decreased methylation of histone H3 Lys(9) in accordance with recovered transcription. This study shows that halogenated thymidines have an antisilencing effect without changing DNA methylation status by interfering with step(s) between DNA methylation and histone acetylation.

  125. RNase S complex bearing arginine-rich peptide and anti-HIV activity 査読有り

    S Futaki, Nakase, I, T Suzuki, D Nameki, EI Kodama, M Matsuoka, Y Sugiura

    JOURNAL OF MOLECULAR RECOGNITION 18 (2) 169-174 2005年3月

    出版者・発行元:JOHN WILEY & SONS LTD

    DOI: 10.1002/jmr.725  

    ISSN:0952-3499

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    Basic peptide-mediated protein delivery into living cells is becoming recognized as a potent approach for the understanding of cellular mechanisms and drug delivery. We have prepared the conjugates of the S-peptide (1-15) derived from RNase S with membrane-permeable basic peptides, octaarginine and the human immunodeficient virus (HIV)-1 Rev (34-50). The RNase S complexes, formed among these S-peptide (1-15)basic peptide conjugates and the S-protein and having a dissociation constant in the range of 10(-5) (M), efficiently penetrated into the HeLa cells. These RNase S complexes exerted an anti-HIV replication activity. The time-of-drug-addition assay suggested that the site of action for these complexes would reside in the stages between the viral entry into the cells and reverse transcription. The present study exemplified the applicability of the arginine-rich peptides to the intracellular targeting of non-covalent protein complexes and supramolecular assemblies for the research in chemical and cellular biology. Copyright (c) 2004 John Wiley B Sons, Ltd.

  126. Mutations conferring resistance to human immunodeficiency virus type 1 fusion inhibitors are restricted by gp41 and Rev-responsive element functions 査読有り

    Daisuke Nameki, Eiichi Kodama, Mieko Ikeuchi, Naoto Mabuchi, Akira Otaka, Hirokazu Tamamura, Mutsuhito Ohno, Nobutaka Fujii, Masao Matsuoka

    Journal of Virology 79 (2) 764-770 2005年1月

    DOI: 10.1128/JVI.79.2.764-770.2005  

    ISSN:0022-538X

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    One of the human immunodeficiency virus (HIV) envelope proteins, gp41, plays a key role in HIV fusion. A gp41-derived peptide, T-20, efficiently inhibits HIV fusion and is currently approved for treatment of HIV-infected individuals. Although resistant variants have been reported, the mechanism of the resistance remains to be defined. To elucidate the mechanism in detail, we generated variants resistant to C34, a peptide derived from the gp41 carboxyl terminus heptad repeat (C-HR) in vitro. The resistant variants had a 5-amino-acid deletion in gp120 and a total of seven amino acid substitutions in gp41. Binding assays revealed that an I37K substitution in the N-terminal heptad repeat (N-HR) impaired the binding of C34, whereas an N126K. substitution in the C-HR enhanced the binding to mutated N-HR, indicating that both mutations were directly involved in resistance. On the other hand, substitutions for A30 and D36 seemed to be secondary mutations, located complementary to each other in the Rev-responsive element (RRE), and were mutated simultaneously to maintain the secondary structure of the RRE that was impaired by the mutations at I37. Thus, HIV acquired resistance to C34 by mutations in N-HR, which directly interacted with C34. However, since this region also encoded the RRE, additional mutations were required to maintain viral replication. These results suggest that HIV fusion is one of the attractive targets for HIV chemotherapy.

  127. Mutations conferring resistance to human immunodeficiency virus type 1 fusion inhibitors are restricted by gp4l and rev-responsive element functions 査読有り

    D Nameki, E Kodama, M Ikeuchi, N Mabuchi, A Otaka, H Tamamura, M Ohno, N Fujii, M Matsuoka

    JOURNAL OF VIROLOGY 79 (2) 764-770 2005年1月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/JVI.79.2.764-770.2005  

    ISSN:0022-538X

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    One of the human immunodeficiency virus (HIV) envelope proteins, gp41, plays a key role in HIV fusion. A gp41-derived peptide, T-20, efficiently inhibits HIV fusion and is currently approved for treatment of HIV-infected individuals. Although resistant variants have been reported, the mechanism of the resistance remains to be defined. To elucidate the mechanism in detail, we generated variants resistant to C34, a peptide derived from the gp41 carboxyl terminus heptad repeat (C-HR) in vitro. The resistant variants had a 5-amino-acid deletion in gp120 and a total of seven amino acid substitutions in gp41. Binding assays revealed that an 137K substitution in the N-terminal heptad repeat (N-HR) impaired the binding of C34, whereas an N126K substitution in the C-HR enhanced the binding to mutated N-HR, indicating that both mutations were directly involved in resistance. On the other hand, substitutions for A30 and D36 seemed to be secondary mutations, located complementary to each other in the Rev-responsive element (RRE), and were mutated simultaneously to maintain the secondary structure of the RRE that was impaired by the mutations at 137. Thus, HIV acquired resistance to C34 by mutations in N-HR, which directly interacted with C34. However, since this region also encoded the RRE, additional mutations were required to maintain viral replication. These results suggest that HIV fusion is one of the attractive targets for HIV chemotherapy.

  128. Studies of nonnueleoside HIV-1 reverse transcriptase inhibitors. Part 1: Design and synthesis of thiazolidenebenzenesulfonamides 査読有り

    N Masuda, O Yamamoto, M Fujii, T Ohgami, J Fujiyasua, T Kontani, A Moritomo, M Orita, H Kurihara, H Koga, H Nakahara, S Kageyama, M Ohta, H Inoue, T Hatta, H Suzuki, K Sudo, Y Shimizu, E Kodama, M Matsuoka, M Fujiwara, T Yokota, S Shigeta, M Baba

    BIOORGANIC & MEDICINAL CHEMISTRY 12 (23) 6171-6182 2004年12月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2004.08.050  

    ISSN:0968-0896

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    A random high-throughput screening (HTS) program to discover novel normucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out with MT-4 cells against a nevirapine-resistant virus, HIV-1(IIIB-R). The primary hit, a thiazolidene-benzenesulfonamide derivative, possessed good activity. A systematic modification program examining various substituents at the 3-, 4-, and 5-positions on the thiazole ring afforded compounds with enhanced anti-HIV-1 and reverse transcriptase (RT) inhibitory activities. These results confirm the important role of the substituents at these positions and the thiazolidenebenzenesulfonamide motif as a valuable lead series for the next generation NNRTIs. (C) 2004 Elsevier Ltd. All rights reserved.

  129. Novel patterns of nevirapine resistance-associated mutations of human immunodeficiency virus type 1 in treatment-naive patients 査読有り

    A Hachiya, H Gatanaga, E Kodama, M Ikeuchi, M Matsuoka, S Harada, H Mitsuya, S Kimura, S Oka

    VIROLOGY 327 (2) 215-224 2004年10月

    出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE

    DOI: 10.1016/j.virol.2004.07.001  

    ISSN:0042-6822

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    Several reports have recently shown that drug-resistant human immunodeficiency virus type 1 (HIV-1) is often isolated from treatment-naive patients. We phenotypically analyzed HIV-1 strains isolated from 44 treatment-naive individuals and found two strains highly resistant (69- and &gt;310-fold) against nevirapine (NVP). Direct sequencing showed these two isolates had a novel mutation, K238S, in reverse transcriptase (RT), but did not have any reported NVP resistance-associated mutation. A 48-h culture in the presence of NVP, however, selected HIV-1 carrying NVP resistance-associated mutations, V106A, V1081, or both, suggesting that minor viral populations of these two isolates had harbored these mutations. Replication kinetic studies of recombinant HIV-1 clones suggested that K238S conferred a significant resistance against NVP, especially when accompanied with V106A (530-fold) or V1081 (56-fold). Our study identified a novel NVP resistance-associated mutation, K238S, which could be persistently detected by genotypic assay longer than V106A and V1081 during off-treatment period. (C) 2004 Elsevier Inc. All rights reserved.

  130. Design, efficient synthesis, and anti-HIV activity of 4 '-C-cyano- and 4 '-C-ethynyl-2 '-deoxy purine nucleosides 査読有り

    S Kohgo, K Yamada, K Kitano, Y Iwai, S Sakata, N Ashida, H Hayakawa, D Nameki, E Kodama, M Matsuoka, H Mitsuya, H Ohrui

    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 23 (4) 671-690 2004年4月

    出版者・発行元:MARCEL DEKKER INC

    DOI: 10.1081/NCN-120037508  

    ISSN:1525-7770

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    Some 4'-C-ethynyl-2'-deoxy purine nucleosides showed the most potent anti-HIV activity among the series of 4'-C-substituted 2'-deoxynucleosides whose 4'-C-substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C-4' position they have, the more acceptable biological activity they show. Thus, 4'-C-cyano-2'-deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4'-C-cyano-2'-deoxy purine nucleosides (4'-CNdNs) and 4'-C-ethynyl-2'-deoxy purine nucleosides (4'-EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2'-deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C-4' position of the sugar moiety from 2'-deoxyadenosine and 2,6-diaminopurine 2'-deoxyriboside. Unfortunately, 4'-C-cyano derivatives showed lower activity against HIV-1, and two 4'-C-ethynyl derivatives suggested high toxicity in vivo.

  131. Application of oligoarginine for the delivery of protein complexes into living cells 査読有り

    Futaki Shiroh, Nakase Ikuhiko, Niwa Miki, Suzuki Tomoki, Nameki Daisuke, Kodama Ei-ichi, Matsuoka Masao, Sugiura Yukio

    Peptide Revolution: Genomics, Proteomics & Therapeutics 791-792 2004年

  132. Attempt to reduce cytotoxicity by synthesizing the L-enantiomer of 4′-C-ethynyl-2′-deoxypurine nucleosides as antiviral agents against HIV and HBV 査読有り

    Kenji Kitano, Satoru Kohgo, Kohei Yamada, Shinji Sakata, Noriyuki Ashida, Hiroyuki Hayakawa, Daisuke Nameki, Eiichi Kodama, Masao Matsuoka, Hiroaki Mitsuya, Hiroshi Ohrui

    Antiviral Chemistry and Chemotherapy 15 (3) 161-167 2004年

    出版者・発行元:International Medical Press Ltd

    DOI: 10.1177/095632020401500306  

    ISSN:0956-3202

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    We investigated the potential of 4′-C-substituted nucleosides for the treatment of HIV-1 and HBV. Of the nucleosides we prepared, several 4′-C-ethynyl-2′-deoxypurine nucleosides showed the most potent anti-HIV activity. However, two candidates, 4′-C-ethynyl-2′- deoxyguanosine and 9-(2-deoxy-4-C-ethynyl-β-D-ribo-pentofuranosyl)-2,6- diaminopurine, were very toxic during in vivo study. On the other hand, lamivudine (3TC) is known to show remarkable activity against HIV and HBV with lower cytotoxicity. Therefore, we attempted to synthesize the L-enantiomer of 4′-C-ethynyl-2′-deoxypurine nucleosides in 20-21 steps. These methods consisted of preparing 4-C-ethynyl-L-sugar, starting from D-arabinose and then condensing the L-sugar derivative with 2,6-diaminopurine. 4″-C-Ethynyl-2′-deoxyguanosine was also prepared by enzymatic deamination from the 2,6-diaminopurine derivative. The compounds' antiviral activity against HIV and HBV was then evaluated. Unfortunately, they demonstrated no activity and no cytotoxicity.

  133. Broad spectrum anti-RNA virus activities of titanium and vanadium substituted polyoxotungstates 査読有り

    S Shigeta, S Mori, E Kodama, J Kodama, K Takahashi, T Yamase

    ANTIVIRAL RESEARCH 58 (3) 265-271 2003年5月

    出版者・発行元:ELSEVIER SCIENCE BV

    DOI: 10.1016/S0166-3542(03)00009-3  

    ISSN:0166-3542

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    Seven polyoxotungstates substituted with vanadium or titanium atoms were examined for their activity against Flaviviridae (Dengue fever virus. DFV), Orthomyxoviridae (influenza virus type A, fluV-A), Paramyxoviridae (respiratory syncytial virus, RSV, parainfluenza virus type 2, PfluV-2 and canine distemper virus, CDV) and Lentiviridae (human immunodeficiency virus type 1, HIV-1) families. Among the seven polyoxotungstates examined, PM-43 {K-5[SiVW11O40]}, PM-47 {K-7[BVW11O40]}, and PM-1001 [K10Na(VO)(3)(SbW9O33)(2)]26H(2)O contained vanadium. PM-1002 had the same core structure of (VO)(3)(SbW9O33)(2) as PM-1001; however, three V atoms of PM-1001 consisted of two V-IV and one V-V and those of PM-1002 consisted of three V-IV. On the other hand, PM-518 {[Et2NH2](7)[PTi2W10O40]}, PM-520 [Pri(2)NH(2)](5)[PTiW11O40] and PM-523 [PriNH(3)](6)H[PTi2W10O38(O-2)(2)]H2O all contained titanium. All compounds showed broad spectrum antiviral activity against all viruses examined except for PMs-43, -518 and -523 which did not exhibit inhibitory activity at greater than or equal to50 muM against PfluV-2. CDV and DFV, respectively. All compounds were inhibitory against HIV replication at an EC50 of less than 2.0 muM. Among them, PMs-1001 and -1002 showed the most potent inhibition. The compounds were not toxic for MDCK, HEp-2 and Vero cells at a concentration of 200 muM. For the exponentially growing MT-4 cells, the vanadium containing polyoxometalates (PMs-43, 47, 1001, 1002) showed toxicity at concentrations between 41 and 47 muM. On the other hand, titanium containing polyoxometalates (PMs-518, -520,-523) were not toxic at 100 muM. The mechanism of anti-HIV action of PM-1001 was analyzed: it affected the binding of HIV to the cell membrane and syncytium formation between HIV-infected and uninfected cells. (C) 2003 Elsevier Science B.V. All rights reserved.

  134. Development of Fusion-inhibiting Anti-HIV-1 Peptides Based on the Structure of Molecular Complex Involved in HIV-1-cell Fusion 査読有り

    Akira Otaka, Miki Nakamura, Eiichi Kodama, Syota Nakamura, Hiroaki Nakano, Susumu Uchiyama, Hirokazu Tamamura, Masao Matsuoka, Yuji Kobayashi, Nobutaka Fujii

    Peptide Science 2002 Vol.2002 (No.0) 65-68 2003年2月1日

    ISSN:1344-7661

  135. Synthesis of 4'-C-ethynyl and 4'-C-cyano purine nucleosides from natural nucleosides and their anti-HIV activity 査読有り

    S Kohgo, K Yamada, K Kitano, S Sakata, H Hayakawa, D Nameki, E Kodama, M Matsuoka, H Mitsuya, H Ohrui

    NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 22 (5-8) 887-889 2003年

    出版者・発行元:MARCEL DEKKER INC

    DOI: 10.1081/NCN-120022678  

    ISSN:1525-7770

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    Purine 2'-deoxynucleosides bearing an ethynyl or a cyano group at C-4' of the sugar moiety were synthesized from the corresponding 2'-deoxynucleosides. These compounds exhibited very potent anti-HIV activity, and remained active against drug resistant HIV strains.

  136. Assuring interoperability in heterogeneous, autonomous and decentralized multi-agent systems 査読有り

    H Suguri, E Kodama, M Miyazaki

    ISADS 2003: SIXTH INTERNATIONAL SYMPOSIUM ON AUTONOMOUS DECENTRALIZED SYSTEMS, PROCEEDINGS 17-24 2003年

    出版者・発行元:IEEE COMPUTER SOC

    DOI: 10.1109/ISADS.2003.1193928  

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    Multi-agent systems are autonomous decentralized platform software on which application programs such as business transactions, network provisioning and manufacturing control are deployed. In order for the applications to be truly autonomous and decentralized, however, heterogeneous multi-agent systems themselves must communicate and interoperate with each other. To solve the problem, we take a two-step approach. Firstly, message-level interoperability is achieved by a gateway agent that interconnects heterogeneous multi-agent systems. Secondly, higher-level interoperation of conversations, which consist of bi- (or multi-) directional streams of messages, is governed by interaction protocols. We demonstrate the concept and technique of dynamic negotiation of interaction protocols and show how the method improves the assurance of real-world applications in autonomous decentralized systems.

  137. Design and Synthesis of Highly Active Anti-HIV Peptide Based on gp41-C34 Peptide 査読有り

    Miki Nakamura, Akira Otaka, Eiichi Kodama, Masao Matsuoka, Susumu Uchiyama, Syota Nakamura, Yuji Kobayashi, Hirokazu Tamamura, Nobutaka Fujii

    Peptide Science 2001 Vol.2001 (No.0) 73-76 2002年3月1日

    ISSN:1344-7661

  138. Artificial Remodeling of gp41-C34 Peptide Leads to Effective HIV Fusion Inhibitor with High anti-HIV Activity 査読有り

    Akira Otaka, Miki Nakamura, Eiichi Kodama, Susumu Uchiyama, Hirokazu Tamamura, Yuji Kobayashi, Masao Matsuoka, Nobutaka Fujii

    Peptide 2002 838-839 2002年

  139. Remodeling of gp41-C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells 査読有り

    A Otaka, M Nakamura, D Nameki, E Kodama, S Uchiyama, S Nakamura, H Nakano, H Tamamura, Y Kobayashi, M Matsuoka, N Fujii

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 41 (16) 2938-2940 2002年

    出版者・発行元:WILEY-V C H VERLAG GMBH

    DOI: 10.1002/1521-3773(20020816)41:16<2937::AID-ANIE2937>3.0.CO;2-J  

    ISSN:1433-7851

  140. Assuring interoperability between heterogeneous multi-agent systems with a gateway agent 査読有り

    H Suguri, E Kodama, M Miyazaki, Kaji, I

    7TH IEEE INTERNATIONAL SYMPOSIUM ON HIGH ASSURANCE SYSTEMS ENGINEERING, PROCEEDINGS 167-170 2002年

    出版者・発行元:IEEE COMPUTER SOC

    DOI: 10.1109/HASE.2002.1173118  

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    In this research, we address the problem of communications lack between heterogeneous multi-agent systems. For example, KQML-based agent cannot talk to FIPA-based agent and vice versa. The authors have identified three main reasons why different multi-agent systems are not interoperable, which we call I architectural elements': (1) inconsistent mental state structures; (2) different syntax and semantics of the agent communication languages; and (3) incompatible message transport mechanisms. To solve this problem, we propose a gateway agent as a translator of the agent If communications that assures the integration of heterogeneous multi-agent systems. We have developed a prototype of the gateway agent that can translate messages between KQML agent and FIPA agent. Based on the results, we are studying a higher level of interoperability based on conversation protocols between agents.

  141. Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140 査読有り

    H Tamamura, A Omagari, K Hiramatsu, K Gotoh, T Kanamoto, YN Xu, E Kodama, M Matsuoka, T Hattori, N Yamamoto, H Nakashima, A Otaka, N Fujii

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 11 (14) 1897-1902 2001年7月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/S0960-894X(01)00323-7  

    ISSN:0960-894X

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    We previously reported a truncated polyphemusin peptide analogue, T140, which efficiently inhibits infection of target cells by T-cell line-tropic strains of HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor. CXCR4. We have found that T140 is not stable in feline serum due to the cleavage of the C-terminal Arg,(14) indispensable for anti-HIV activity. On the other hand, a C-terminally amidated analogue of T140, TZ14004, has been found to be completely stable in incubation in the serum for 2 days. The C-terminal amide is thought to be needed for stability in serum. However. TZ14004 does not have fairly strong anti-HIV activity, but has relatively strong cytotoxicity, probably due to an increase by + 1 charge from total + 7 charges of T140. In our previous study, the number of total + 6 charges seemed to be a suitable balance between activity and cytotoxicity. In this study, we have conducted a double-L-citrulline (Cit)-scanning study on TZ14004 based on the C-terminally amidated form in due consideration of the total net charges in the whole molecule to find novel effective CXCR4 inhibitors, TN14003 ([Cit(6)]-T140 with the C-terminal amide) and TC14012 ([Cit(6), D-Cit(8)]-T140 with the C-terminal amide), which possess high selectivity indexes (SIs) and complete stability in feline serum. (C) 2001 Elsevier Science Ltd. All rights reserved.

  142. 4 '-ethynyl nucleoside analogs: Potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro 査読有り

    EI Kodama, S Kohgo, K Kitano, H Machida, H Gatanaga, S Shigeta, M Matsuoka, H Ohrui, H Mitsuya

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 45 (5) 1539-1546 2001年5月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/AAC.45.5.1539-1546.2001  

    ISSN:0066-4804

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    A series of 4 ' -ethynyl (4 ' -E) nucleoside analogs were designed, synthesized, and identified as being active against a wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined, 4 ' -E-2 ' -deoxycytidine (4 ' -E-dC), 4 ' -E-2 ' -deoxyadenosine (4 ' -E-dA), 4 ' -E-2 ' -deoxyribofuranosyl-2,6-diamifiopurine and 4 ' -E-2 ' -deoxyguanosine were the most potent and blocked HIV-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 muM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4 ' -E analogs also suppressed replication of various drug-resistant HIV-I clones, including HIV-I,,,,,, HIV-1K(65R), HIV-1(L74V), HIV-1(M41/T69S-S-G/T215Y), and HIV-1(A62V/V75I/F77L/F116Y/Q151M). Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4 ' -E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1(Y181C), and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4 ' -E-thymidine and 4 ' -E-dC was blocked by the addition of thymidine and 2 ' -deoxycytidine, respectively, while that of 4 ' -E-dA was not affected by 2 ' -deoxyadenosine, similar to the antiviral activity reversion feature of 2 ' ,3 ' -dideoxynucleosides, strongly suggesting that 4 ' -E analogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4 ' -E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted.

  143. 4′-Ethynyl nucleoside analogues: Potent inhibitors active against multi-drug-resistant HIV variants 査読有り

    Kodama E, Matsuoka M, Ohrui H, Mitsuya H

    International Antiviral News 9 (8) 128-132 2001年

  144. Syntheses of 4 '-C-ethynyl-beta-D-arabino- and 4'-C-ethynyl-2'-deoxy-beta-D-ribo-pentofuranosylpyrimidines and -purines and evaluation of their anti-HIV activity 査読有り

    H Ohrui, S Kohgo, K Kitano, S Sakata, E Kodama, K Yoshimura, M Matsuoka, S Shigeta, H Mitsuya

    JOURNAL OF MEDICINAL CHEMISTRY 43 (23) 4516-4525 2000年11月

    出版者・発行元:AMER CHEMICAL SOC

    DOI: 10.1021/jm000209n  

    ISSN:0022-2623

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    4'-C-Ethynyl-beta -D-arabino- and 4'-C-ethynyl-2'-deoxy-beta -D-ribo-pentofuranosylpyrine and -purine nucleosides were synthesized and evaluated for their in vitro anti-HIV activity. The key intermediate, 4-C-ethynyl- or 4-C-triethylsilylethynyl-D-ribo-pentofuranose, was prepared from D-glucose and glycosidated with various pyrimidine or purine bases. The arabino pyrimidine derivatives were prepared from the corresponding ribo derivatives via O-2,2'-anhydro nucleosides. The 2'-deoxy-ribo derivatives were synthesized by radical reduction of 2'-bromo or 2'- phenoxythiocarbonyloxy nucleosides. Among these 4'-C-ethynyl nucleosides, seven analogues proved to be potent against HIV-1 in vitro with EC50 values ranging from 0.0003 to 0.03 muM. These compounds also exerted activity against clinical and multi-dideoxy-nucleoside-resistant HIV-1 strains with comparable EC50 values. Three such 4'-C-ethynyl-2'-deoxypurine analogues including 4'-C-ethynyl-2'-deoxyadenosine and 4'-C-ethynyl-2,6-diamino-2'-deoxy-purine were less cytotoxic [selectivity indices (SIs): 975-2733] than three 4'-C-ethynyl-2-deoxycytidine analogues (SIs: 63-363). 4'-C-Ethynyl-5-fluoro-2'-deoxycytidine was least toxic (SI: &gt;3333) and potent against all HIV strains tested.

  145. 140(P-96) 多剤耐性HIVに有効なヌクレオシドの創製(ポスター発表の部)

    向後 悟, 大類 洋, 北濃 健司, 児玉 栄一, 満屋 裕明

    天然有機化合物討論会講演要旨集 (42) 835-840 2000年10月1日

    出版者・発行元:天然有機化合物討論会

    DOI: 10.24496/tennenyuki.42.0_835  

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    4'-C-Ethynyl-β-D-arabino- and 4'-C-ethyny1-2'-deoxy-β-D-ribo-pentofuranosyl pyrimidine and purine nucleosides were synthesized, and evaluated for their in vitro anti-HIV activity. The key intermediate, 4-C-ethynyl or 4-C-triethylsilylethynyl-α-D-ribo-pentofuranose, was prepared from D-glucose and glycosidated with various pyrimidine or purine bases. The arabino pyrimidine derivatives were prepared from the corresponding ribo derivatives via O^2-2'-cyclonucleosides. The 2'-deoxyribo derivatives were synthesized by radical reduction of 2'-bromo or 2'-phenoxythio-carbonyloxy nucleosides. These 4'-C-ethynyl nucleosides were proved to be potent against HIV-1 in vitro with EC_<50> values ranging 0.0003 to 0.61μM. These compounds also exerted an activity against multi-dideoxynucleoside-resistant HIV-1 strains with comparable EC_<50> values.

  146. Interactions of conformationally biased north and south 2 '-fluoro-2 ',3 '-dideoxynucleoside 5 '-triphosphates with the active site of HIV-1 reverse transcriptase 査読有り

    L Mu, SG Sarafianos, MC Nicklaus, P Russ, MA Siddiqui, H Ford, H Mitsuya, R Le, E Kodama, C Meier, T Knispel, L Anderson, JJ Barchi, VE Marquez

    BIOCHEMISTRY 39 (37) 11205-11215 2000年9月

    出版者・発行元:AMER CHEMICAL SOC

    DOI: 10.1021/bi001090n  

    ISSN:0006-2960

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    Molecular dynamics simulations of a ternary complex of HIV-1 reverse transcriptase (RT), double-stranded DNA, and bound dideoxynucleoside-5'-triphosphate (RT-DNA-ddNTP), utilizing the ddNTPs ddATP, beta FddATP, and alpha FddATP, explain the experimentally observed order of potency of these 5'-triphosphates as inhibitors of RT: ddATP &gt; beta FddATP &gt; alpha FddATP. On the basis of RT's known preference to bind the incoming dNTP (or ddNTP) with a north conformation at the polymerase site, alpha FddATP, which in solution prefers almost exclusively a north conformation, was predicted to be the most potent inhibitor. However, Tyr115, which appears to function as a steric gate to preclude the binding of ribonucleoside 5'-triphosphates, prevents the effective binding of alpha FddATP in its preferred north conformation. The south-biased beta FddATP, while able to bind to RT without hindrance by Tyr115, has to pay a high energy penalty to be flipped to the active north conformation at the polymerase site. Finally, the more flexible and less conformationally biased ddATP is able to switch to a north conformation at the RT site with a smaller energy penalty than beta FddATP. These results highlight the opposite conformational preferences of HIV-1 RT for alpha FddATP and beta FddATP and help establish conformational guidelines for optimal binding at the polymerase site of this enzyme.

  147. Synthesis of 4'-ethynyl-purine nucleosides possessing anti-HIV activity. 査読有り

    Kitano K, Sakata S, Kohgo S, Matsuoka M, Kodama E, Mitsuya H, Ohrui H

    Nucleic Acids Symp Ser (44) 105-106 2000年4月

  148. Antileukemic activity and mechanism of action of cordycepin against terminal deoxynucleotidyl transferase-positive (TdT(+)) leukemic cells 査読有り

    EN Kodama, RP McCaffrey, K Yusa, H Mitsuya

    BIOCHEMICAL PHARMACOLOGY 59 (3) 273-281 2000年2月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/S0006-2952(99)00325-1  

    ISSN:0006-2952

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    The nucleoside analogue cordycepin (3'-deoxyadenosine, 3'-dA) is substantially more cytotoxic to terminal deoxynucleotidyl transferase positive (TdT(+)) leukemic cells than to TdT(-) leukemic cells in vitro in the presence of an adenosine deaminase inhibitor, deoxycoformycin (dCF), and has been considered as a therapeutic agent for TdT(+) leukemia. The intracellular metabolism of 3'-dA was examined with HPLC, and the mechanism of its anti-TdT(+) leukemic activity was analyzed. In the presence of dCF (2.5 mu M), TdT(+) leukemic cells (N = 5) were sensitive to the cytotoxic effect of 3' dA, whereas TdT(-) (N = 6) cells were not. A high level of 3'-dA-5'-triphosphate (3'-dATP) formation was detected in TdT(+) NALM-6 cells (67 pmol/10(6) cells) and TdT(-) K562 cells (49 pmol/10(6) cells) when cultured with 1 mu M [3'-H-3]-labeled 3'-dA. A substantial level of 3'-dATP was detected in TdT(-) HUT-102 cells (27 pmol/10(6) cells), whereas the level of 3'-dATP in TdT(+) MOLT-4 cells was low (0.3 pmol/10(6) cells). The mean Ic(50) values of 3'-dA against phytohemagglutinin (PHA)-activated and resting peripheral blood mononuclear cells (PBM) (N = 5) were 8 and 32 mu M, respectively. There was a modest level of 3'-dATP (7 pmol/10(6) cells) in PHA-PBM, whereas a lower level of 3'-dATP was detected in resting PBM (2.5 pmol/10(6) cells). These data suggest that the presence of 3'-dATP is not sufficient for the antileukemic effect of 3'-dA, but that TdT positivity is essential, and that PBM are significantly less sensitive to the cytotoxicity of 3' dA in vitro. Further development of 3'-dA as a potential antileukemic agent to treat patients with TdT(+) leukemia is warranted. (C) 1999 Elsevier Science Inc.

  149. Natural language programming for multimedia information 査読有り

    E Kodama, K Sato, M Miyazaki

    SEVENTH INTERNATIONAL CONFERENCE ON PARALLEL AND DISTRIBUTED SYSTEMS: WORKSHOPS, PROCEEDINGS 167-172 2000年

    出版者・発行元:IEEE COMPUTER SOC

    DOI: 10.1109/PADSW.2000.884533  

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    Learning a programming language is difficult for the beginner of the computer. Therefore, it is necessary to build an intelligent programming environment in which the program can be written directly in the grammar of one's mother tongue. In this paper, we propose a model of an intelligent programming environment that is oriented to the Japanese. In this model, the text that describes in Japanese the layout of multimedia contents and the relationship between two multimedia contents can be parsed with the technology of machine translation, translated into an executable program, and executed. As an application of the proposed model, an environment culled ACORNS is implemented. The performance study of ACORNS is performed. The results of the performance study shows that the proposed model is robust.

  150. Characterization of human immunodeficiency virus type 1 strains resistant to the non-nucleoside reverse transcriptase inhibitor RD4-2217 査読有り

    M Fujiwara, EN Kodama, M Okamoto, K Tokuhisa, T Ide, Y Hanasaki, K Katsuura, H Takayama, N Aimi, H Mitsuya, S Shigeta, K Konno, T Yokota, M Baba

    ANTIVIRAL CHEMISTRY & CHEMOTHERAPY 10 (6) 315-320 1999年11月

    出版者・発行元:INT MEDICAL PRESS

    ISSN:0956-3202

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    The non-nucleoside reverse transcriptase (RT) inhibitor RD4-2217 is a thiadiazole derivative that has proved to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in vitro. In this study we examined genotypic and phenotypic characteristics of RD4-2217-resistant mutants that have been obtained by serial passage of HIV-1 in MT-4 cells in the presence of increasing concentrations (0.05, 0.25, 1 and 10 mu M) of the compound. The strains obtained, IIIB/2217RE/0.05 and IIIB/2217RE/0.25, were two- and 15-fold resistant to RD4-2217, respectively, whereas IIIB/2217RE/1 and IIIB/2217RE/10 displayed 161- and &gt;238-fold resistance, respectively. Both IIIB/2217RE/1 and IIIB/2217RE/10 had two amino acid substitutions, V1891 and T2401, in the Furthermore, RD4-2217 did not inhibit the replication of an HIV-1 molecular clone, which had the same mutation, at concentrations up to 10 mu M, indicating that the V1891 plus T2401 mutation confers high-level resistance to RD4-2217. Interestingly, the replicability of IIIB/2217RE/1 and IIIB/2217RE/10 appeared to be lower than that of wild-type IIIB in MT-4 cells, suggesting that the plus T2401 mutation may impair the enzymatic activity of HIV-1 RT.

  151. In vitro induction of human immunodeficiency virus type 1 variants resistant to phosphoralaninate prodrugs of Z-methylenecyclopropane nucleoside analogues 査読有り

    K Yoshimura, R Feldman, E Kodama, MF Kavlick, YL Qiu, J Zemlicka, H Mitsuya

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 43 (10) 2479-2483 1999年10月

    出版者・発行元:AMER SOC MICROBIOLOGY

    ISSN:0066-4804

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    Two methylenecyclopropane nucleoside analogues with a phenylphosphoralaninate moiety, QYL-685 and QYL-609, exert potent and specific activities against human immunodeficiency virus type 1 strain LAI (HIV-1(LAI)) and HIV-2 in vitro. In this study, we induced HIV-1 variants resistant to QYL-685 by exposing HIV-1(LAI) to increasing concentrations of QYL-685, After 16 passages, the virus (HIV-1(P16)) was less sensitive to QYL-685 (104-fold), QYL-609 (&gt;41-fold), and (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC) (&gt;1,100-fold) than was HIV-1, and contained an M184I mutation. Two infectious clones, HIV-1(M184I) and HIV-1(M184V) were resistant to QYL-685, QYL-609, and 3TC, confirming that the M184I mutation was responsible for the observed resistance. Viral-fitness analyses (competitive HIV-1 replication assays) revealed that in the absence of drugs, R M184I and M184V conferred a replication disadvantage on the virus compared to the replication efficiency of the wild-type infectious clone (HIV-1(wt)). However, in the presence of QYL-685 (4 mu M), HIV-1(M184I) and HIV-1(M184V) showed greater fitness than HIV-1,. These data may provide structural and virological relevance with regard to the emergence of M184I and M184V substitutions in HIV-1.

  152. Significance of endogenous heat shock protein in adjuvant arthritis 査読有り

    M Miyata, H Sato, H Sato, Y Sato, E Kodama, R Kasukawa

    JOURNAL OF RHEUMATOLOGY 26 (10) 2210-2214 1999年10月

    出版者・発行元:J RHEUMATOL PUBL CO

    ISSN:0315-162X

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    Objective. To investigate the role of endogenous heat shock protein (HSP) (rat 60 kDa HSP, rHSP 60) in adjuvant arthritis (AA), the expression of rHSP 60 in AA-susceptible Lewis rats and AA-resistant Fisher rats was studied. Methods. The extent of arthritis was assessed by measuring footpad thickness, The proliferative response of mononuclear cells (MNC) to mycobacterial 65 kDa HSP (mHSP 65) was measured by [H-3] thymidine incorporation. The messenger RNA for rHSP 60 was quantified by dot blot hybridization in peripheral blood mononuclear cells (PBMNC), splenic MNC (SMNC), and ankle joint synovial membrane (SM), Results. In Lewis rats: AA developed on Day 14 after immunization with Freund's complete adjuvant, Proliferative responses of PBMNC and SMNC to mHSP 65 were observed on Day 14 and thereafter according to the development of AA. Messenger RNA levels of rHSP 60 in PBMNC, SMNC, and SM did not increase until Day 21. In Fisher rats: AA and proliferative response of MNC to mHSP 65 were not observed throughout the observation period. Messenger RNA levels of rHSP 60 were significantly higher in preimmune Fisher rats than those in preimmune Lewis rats. Messenger RNA levels of rHSP 60 in PBMNC and SMNC increased significantly on Day 7 and decreased to preimmune levels until Day 21. Conclusion. We propose that elevated levels and rapid elevation of endogenous HSP 60 levels relate to resistance to AA in Fisher rats; however, lower levels and delayed increase of endogenous HSP 60 levels relate to susceptibility to AA in Lewis rats.

  153. Anti-herpesvirus activities and cytotoxicities of 2-thiopyrimidine nucleoside analogues in vitro 査読有り

    S Shigeta, S Mori, T Kira, K Takahashi, E Kodama, K Konno, T Nagata, H Kato, T Wakayama, N Koike, M Saneyoshi

    ANTIVIRAL CHEMISTRY & CHEMOTHERAPY 10 (4) 195-209 1999年7月

    出版者・発行元:INT MEDICAL PRESS

    DOI: 10.1177/095632029901000404  

    ISSN:0956-3202

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    Twenty 2-thiopyrimidine nucleoside analogues were synthesized and examined for inhibitory activity against herpes simplex virus (HSV) type 1 and 2, varicella-zoster virus (VZV), human cytomegalovirus (HCMV) and thymidine kinase-deficient HSV (HSV-TK-) replication in vitro. 2-thiouracil (thymine) arabinoside, 2'-deoxy-2-thiouridine (or 2-thiothymidine) and their 5-halogenated derivatives showed anti-HSV activity in both RPMI8226 (human B-lymphoblastoid cells) and MRC-5 (human embryo lung cells). 2'-deoxy-5-halogenated-2-thiocytidines were also inhibitory against HSV, whereas 2-thiocytosine arabinoside and its derivatives were not inhibitory against HSV replication, except 5-bromo and 5-iodo congeners (TN-31. TN-32). Substitution of the halogen atom at the 5-position of the pyrimidine rings to an atom with a higher molecular weight increased anti-HSV and VZV activities, except for the anti-HSV activity of 2-thiouracil arabinosides. 2'-deoxy-5-methyl-, and 2'-deoxy-5-iodo-2-thiouridines (TN-17. TN-44) showed the most potent anti-HSV activity, and 2'-deoxy-5-chloro- and 2'-deoxy-5-bromo-2-thiocytidines were potent inhibitors of VZV replication. However, none of the compounds inhibited HCMV and HSV-TK- replication. TN-31 and TN-32 were shown to inhibited HCMV and HSV-TK- as well as HSV and VZV replication. The cytotoxicity of the 2-thio-pyrimidine nucleoside analogues was less than that of the 2-oxy-congeners of the compounds (5-iodo-2'-deoxyuridine, 5-iodo-2'-deoxycytidine, thymine arabinoside and cytosine arabinoside). The selectivity index of 2'-deoxy-5-iodo-thiouridine (TN-44) was higher than that of 5-iodo-deoxyuridine TN-17 and TN-44 were not cytotoxic to resting or stimulated human peripheral blood mononuclear cells at 400 mu M, although TN-32 was cytotoxic at a concentration of 20 mu M.

  154. In vitro anti-human immunodeficiency virus activities of Z- and E-methylenecyclopropane nucleoside analogues and their phosphoro-L-alaninate diesters 査読有り

    H Uchida, EN Kodama, K Yoshimura, Y Maeda, P Kosalaraksa, Maroun, V, YL Qiu, J Zemlicka, H Mitsuya

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 43 (6) 1487-1490 1999年6月

    出版者・発行元:AMER SOC MICROBIOLOGY

    ISSN:0066-4804

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    Nucleoside analogues with a Z- or an E-methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-L-alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 mu M, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multi-dideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.

  155. Synthesis of 4'-substituted nucleosides and their biological evaluation. 査読有り

    Kohgo S, Kodama E, Shigeta S, Saneyoshi M, Machida H, Ohrui H

    Nucleic Acids Symp Ser (42) 127-128 1999年4月

  156. Inhibition of human immunodeficiency virus replication by RD6-Y664, a novel benzylhydroxylamine derivative 査読有り

    M Okamoto, M Fujiwara, E Kodama, O Yamamoto, S Shigeta, H Mitsuya, K Konno, T Yokota, M Baba

    ANTIVIRAL CHEMISTRY & CHEMOTHERAPY 10 (2) 71-77 1999年3月

    出版者・発行元:INT MEDICAL PRESS

    ISSN:0956-3202

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    We have examined novel benzylhydroxylamine derivatives for their inhibitory effects on the replication of human immunodeficiency virus (HIV) in cell cultures. Among the series, O-(2-chloro-6-fluorobenzyl)hydroxylamine (RD6-Y664) was found to be the most potent inhibitor of HIV-1. The EC50 for HIV-1 strain IIIB was 1.6 mu g/ml with a selectivity index greater than 38 in MT-4 cells. It also inhibited the replication of other HIV strains including a non-nucleoside reverse transcriptase (RT) inhibitor-resistant mutant, a nucleoside RT inhibitor-resistant mutant and HIV-2, in acutely infected cells. However, the compound did not affect HIV-1 production in chronically infected cells. A time-of-addition experiment and detection of proviral DNA synthesis suggested that RD6-Y664 targeted an early step of the viral replication cycle, presumably a process prior to reverse transcription. In fact, an assay for HIV-1 RT revealed that the compound did not suppress enzyme activity. Furthermore, RD6-Y664 did not show any inhibition of gp120-CD4 interaction, or binding of anti-CXCR4 antibody to CXCR4.

  157. Marine microalgal polysaccharide induces apoptosis in human lymphoid cells 査読有り

    K Sogawa, E Kodama, M Matsuda, S Shigeta, K Okutani

    JOURNAL OF MARINE BIOTECHNOLOGY 6 (1) 35-38 1998年

    出版者・発行元:SPRINGER VERLAG

    ISSN:0941-2905

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    An extracellular polysaccharide from the marine microalga dinoflagellate Gymnodinium sp, A3, which was a D-galactan sulfate associated with L(+)-lactic acid, showed cytotoxicities to various human lymphoid cells, especially to MT-4 cells (CC50 2.67 mu g/ml). Close observations of morphological change, flow cytometry, and in situ end-labeling of fragmentated DNA revealed the mechanism of cytotoxicity of this polymer to be based on the induction of apoptosis.

  158. Application of a gastric cancer cell line (MKN-28) for anti-adenovirus screening using the MTT method 査読有り

    E Kodama, S Shigeta, T Suzuki, E DeClercq

    ANTIVIRAL RESEARCH 31 (3) 159-164 1996年7月

    出版者・発行元:ELSEVIER SCIENCE BV

    DOI: 10.1016/0166-3542(96)06966-5  

    ISSN:0166-3542

    詳細を見る 詳細を閉じる

    We established a sensitive and accurate method for screening of anti-adenovirus agents using the 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. MKN-28 cells, which are well-differentiated stomach adenocarcinoma cells, were used for adenovirus (ADV) infection and examined for the anti-ADV activities of several established anti-herpes virus agents. ADV-11 is the causative agent of respiratory and urinary infections. It frequently causes hemorrhagic cystitis in immunocompromised hosts. One laboratory strain and 4 clinical isolates of ADV-11 were examined, and found susceptible (in order of decreasing activity) to 2-amino-7-[(1,3-dihydroxy-2-propoxy)melhyl]purine (S-2242), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine[(S)-HPMPA], and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine[(S)-HPMC]. On the other hand, ganciclovir and iododeoxyuridine were only weakly effective and dextran sulfate was ineffective. Our findings indicate that the MTT assay using MKN-28 cells is applicable to anti-ADV screening. The anti-ADV activity of (S)-HPMPA and (S)-HPMPC was confirmed, and, furthermore, S-2242 emerged as a highly potent and selective inhibitor of ADV-11.

  159. Evaluation of antiherpetic compounds using a gastric cancer cell line: Pronounced activity of BVDU against herpes simplex virus replication 査読有り

    E Kodama, A Igarashi, S Mori, KI Hashimoto, T Suzuki, E DeClercq, S Shigeta

    MICROBIOLOGY AND IMMUNOLOGY 40 (5) 359-363 1996年

    出版者・発行元:CENTER ACAD PUBL JAPAN

    ISSN:0385-5600

    詳細を見る 詳細を閉じる

    We developed a rapid and simple method for the screening of antiviral agents against herpes simplex virus (HSV) in a model of gastrointestinal herpetic infection in vitro. This method was based on inhibition of HSV-induced cytopathogenicity in gastric adenocarcinoma MKN-28 cells, as monitored by an MTT colorimetric assay. From the various compounds that were evaluated for their activity against HSV-1 and HSV-2, brivudine (BVDU) emerged as the most effective. When the 50% effective concentration (EC(50)) values of the antiherpes agents in MKN-28 cells were compared with those in human embryo lung MRC-5 cells, all compounds, except for BVDU, showed higher EC(50) values in MKN-28 cells. For BVDU the EC(50) values in MKN-28 cells were 0.8 (HSV-1) and 0.036 (HSV-2) times the EC(50) values in MRC-5 cells. Thus BVDU was 275 times more active against HSV-2 in MKN-28 cells than in MRC-5 cells. The MKN-28 gastric cancer cells may be useful for the rapid screening of anti-HSV agents and, in particular, those that may be useful in therapy of gastrointestinal HSV infections in gastrointestinal herpetic infection.

  160. Antiviral activity of a sulphated polysaccharide extracted from the marine Pseudomonas and marine plant Dinoflagellata against human immunodeficiency viruses and other enveloped viruses 査読有り

    K. Hashimoto, E. Kodama, S. Mori, J. Watanabe, M. Baba, K. Okutani, M. Matsuda, S. Shigeta

    Antiviral Chemistry and Chemotherapy 7 (4) 189-196 1996年

    出版者・発行元:International Medical Press Ltd

    DOI: 10.1177/095632029600700403  

    ISSN:0956-3202

    詳細を見る 詳細を閉じる

    A natural sulphated mucopolysaccharide (OKU40), extracted from a marine plant Dinoflagellata, and an artificial sulphated polysaccharide (OKU41), prepared from a marine Pseudomonas, displayed antiviral activities against several enveloped viruses. OKU40 and OKU41 were found to be homogenous in electrophoresis and sedimation velocity and had a molecular weight of 8.0 x 106 and 5.0 x 106, respectively The sulphation rate of OKU40 and OKU41 was 8.9% and 5.4%, respectively. Each OKU40 and OKU41 inhibited the cytopathic effect of human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2) and zidovudine-resistant HIV-1 in MT-4 cells at similar concentrations to those of dextran sulphate (molecular weight: 5000) (50% inhibitory concentrations: 0.86-1.95 μg mL-1), whereas these compounds did not affect the growth and viability of mock-infected MT-4 cells at concentrations up to 500 μg mL-1. These compounds proved inhibitory not only to HIV-1 and HIV-2 but also to other enveloped viruses, i.e, herpes simplex virus type 1, influenza virus A and B, respiratory syncytial virus and measles virus, OKU40 and OKU41 suppressed syncytium formation induced by cocultivation of MOLT-4/III(B) and MOLT-4 cells at concentrations higher than 20 μg mL-1. Although OKU41 inhibited the binding of HIV-1 to the host cells and the binding of anti-gp120 monoclonal antibody to HIV-1 gp120, OKU40 did not inhibit these bindings, suggesting that the mechanism of anti-HIV activity of OKU40 and OKU41 may be primarily due to the inhibition of virus cell fusion and viral adsorption to the host cells, respectively. Furthermore, these compounds did not inhibit to the blood coagulation process at a concentration that was significantly inhibitory to HIV replication. The compounds appear to have an interesting potential as virucidal agents.

  161. Analysis of human 65 kD heat shock protein mRNA using polymerase chain reaction in synovia of rheumatoid arthritis patients. 査読有り

    Kodama E, Kasukawa R, Miyata M, Shigeta S, Ito M

    Fukushima J Med Sci 41 (2) 95-102 1995年12月

    出版者・発行元:福島県立医科大学

    ISSN:0016-2590

  162. DETECTION OF ANTIBODIES TO 65 KD HEAT-SHOCK PROTEIN AND TO HUMAN SUPEROXIDE-DISMUTASE IN AUTOIMMUNE HEPATITIS-MOLECULAR MIMICRY BETWEEN 65 KD HEAT-SHOCK PROTEIN AND SUPEROXIDE-DISMUTASE 査読有り

    M MIYATA, A KOGURE, H SATO, E KODAMA, H WATANABE, H OHIRA, M KURODA, T TAKAGI, Y SATO, R KASUKAWA

    CLINICAL RHEUMATOLOGY 14 (6) 673-677 1995年11月

    出版者・発行元:ROYAL BELG RHEUMATOL SOC

    ISSN:0770-3198

    詳細を見る 詳細を閉じる

    The antibody to 65 KD mycobacterial heat shock protein (HSP65) and antibody to human superoxide dismutase (H-SOD) were measured by ELISA in patients with autoimmune hepatitis (AIH), and results were compared with those of patients with chronic active hepatitis C (CAH-C) or systemic lupus erythematosus (SLE) and normal subjects (NS). Patients with AIH had significantly higher OD values of anti-HSP65 antibody and anti-H-SOD antibody compared with those of patients with CAH-C or SLE and NS. OD values of anti-HSP65 antibody were correlated with those of anti-SOD antibody. Affinity-purified anti-SOD antibody reacted with HSP65. Analysis of the amino acid sequence of human SOD showed that 7 segments, corresponding to r to 25 amino acid residues, exhibited 50 to 71% homology with that of mycobacterial HSP65.

  163. ANALYSIS OF MUTATIONS IN THE THYMIDINE KINASE GENE OF VARICELLA TESTER VIRUS-ASSOCIATED WITH RESISTANCE TO 5-IODO-2'-DEOXYURIDINE AND 5-BROMO-2'-DEOXYURIDINE 査読有り

    E KODAMA, S MORI, S SHIGETA

    ANTIVIRAL RESEARCH 27 (1-2) 165-170 1995年5月

    出版者・発行元:ELSEVIER SCIENCE BV

    DOI: 10.1016/0166-3542(94)00077-L  

    ISSN:0166-3542

    詳細を見る 詳細を閉じる

    We have analyzed mutations in the thymidine kinase (TK) gene of varicella tester virus (VZV) which showed resistance to 5-iodo-2'-deoxyuridine (IDU) and 5-bromo-2'-deoxyuridine (BrDU). Through sequencing of the TK gene, we found three amino acids were exchanged (41 Asn --&gt; Ser, 266 Cys --&gt; Ile, 288 Ser --&gt; Leu). These mutations were not located at either the nucleoside- or the ATP-binding site. This result suggests that the resistance to IDU and BrDU in this particular strain is due to the change in conformation of TK rather than the replacement of amino acids in the binding sites.

  164. ANTIBODIES TO 65KD HEAT-SHOCK PROTEIN WERE ELEVATED TO RHEUMATOID-ARTHRITIS 査読有り

    A ODA, M MIYATA, E KODAMA, H SATOH, Y SATO, T NISHIMAKI, H NOMAGUCHI, R KASUKAWA

    CLINICAL RHEUMATOLOGY 13 (2) 261-264 1994年6月

    出版者・発行元:ROYAL BELG RHEUMATOL SOC

    ISSN:0770-3198

    詳細を見る 詳細を閉じる

    Antibodies to 65Kd heat-shock protein (hsp) of mycobacterium leprae were measured by enzyme-linked immunosorbent assay (ELISA) in the three immunoglobulin classes in paired sera and synovial fluids of patients with rheumatoid arthritis (RA). Titers of anti-hsp antibody were expressed by optical density (OD) values for sera or indexes (OD values divided by amounts of immunoglobulin in each class) for synovial fluids and for their paired sera. Indexes of anti-hsp antibody were higher in synovial fluids than those in sera at 15/18 for IgG, 17/18 for IgA and 16/18 for IgM class. These results suggest the participation of anti-hsp antibodies to synovitis in RA.

  165. DETECTION OF HEPATITIS-C VIRUS GENOME IN HUMAN SERUM BY MULTITARGETED POLYMERASE CHAIN-REACTION 査読有り

    M OKAMOTO, M BABA, E KODAMA, K SEKINE, T TAKAGI, R KASUKAWA, S SHIGETA

    JOURNAL OF MEDICAL VIROLOGY 41 (1) 6-10 1993年9月

    出版者・発行元:WILEY-LISS

    DOI: 10.1002/jmv.1890410103  

    ISSN:0146-6615

    詳細を見る 詳細を閉じる

    A multi-targeted ''hemi-nested'' PCR (M-PCR) assay in which the primer pairs derived from the 5' non-coding (5'NC) and the nonstructural protein 3 (NS3) regions of HCV genome were concurrently used for amplification in order to compare the sensitivity and specificity of polymerase chain reaction (PCR) with different primer pairs in detecting hepatitis C virus (HCV) genome. Sera from patients with virus-associated liver diseases were examined for the presence of HCV RNA by the M-PCR method following reverse transcription to cDNA. The amplified products derived from both the 5'NC and the NS3 regions were detected in 28 (70%) of the 40 HCV RNA-positive samples. However, 12 samples (30%) were devoid of the signal of NS3-derived product. Sensitivity tests using serial dilutions of HCV RNA revealed that the 5'NC-derived band was still detectable in the 10(5)-fold diluted sample by the M-PCR method, yet the NS3-derived band could hardly be detected in the 10(4)-fold diluted sample. Thus, as previously demonstrated by a single-targeted ''nested'' PCR assay, the present study using the M-PCR assay has clearly shown that the 5'NC-derived primers are more sensitive and specific than the NS3-derived primers in detecting HCV RNA. (C) 1993 Wiley-Liss, Inc.

  166. A case report of transverse myelopathy associated with systemic lupus erythematosus with positive antiphospholipid antibody 査読有り

    Hiroshi Watanabe, Hironobu Ochiai, Eiichi Kodama, Shuzoh Suzuki, Isao Takeda, Noriya Watanabe, Shigeaki One, Shunji Kaise, Tomoe Nishimaki, Reiji Kasukawa

    Japanese Journal of Clinical Immunology 15 (4) 385-390 1992年

    DOI: 10.2177/jsci.15.385  

    ISSN:1349-7413 0911-4300

    詳細を見る 詳細を閉じる

    In November 1986, a 37-year-old female patient was diagnosed as systemic lupus erythematosus (SLE) because of photosensitivity, butterfly rash, positive antinuclear antibody and positive anti DNA antibody, and thereafter she had been treated with prednisolone in the department of dermatology of our college. In Decemmber 1989, she was transferred to our department because of general fatigue and paresis in her both legs. The titers of antinuclear antibody were 1 to 2,560 and anticar-diolipin (aCL) antibody were a titer of 73 U/ml. Her head CT scan showed multiple cerebral infarction and she was treated with prednisolone at initial dosage of 40 mg per day with a slight improvement of clinical symptoms. However, she stopped taking prednisolone by her own will. In May 1990, she was re-admitted because of complete paralysis and sensory disturbance on her both feet and vesico-urethral disturbance with a high titer of aCL antibody (94 U/ml). She was diagnosed as transverse myelopathy associated with SLE with positive aCL antibody. Treatments of pulse therapy with methylprednisolone, oral administration of cyclophosphamide, intravenous administration of γ-globulin as large as 15 g per day for 5 days, and plasma exchange were not effective on neurological symptoms, in spite of decreased titer of aCL. Early treatment seemed to be necessary for clinical improvement of transverse myelopathy. © 1992, The Japan Society for Clinical Immunology. All rights reserved.

︎全件表示 ︎最初の5件までを表示

MISC 123

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    出版者・発行元:(一社)日本看護研究学会

    ISSN:0285-9262

    eISSN:2189-6100

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    本研究は,2016年の熊本地震を経験した医療機関の被害状況の特徴や診療体制,支援体制への影響をもとに,災害時の業務継続に必要な取り組みを考察することを目的とした。熊本地震被害の大きかった地域で,病床数100床以上の病院の看護部長と医療設備担当者を対象に半構造化面接法によるデータ収集を行った。(1)震災による診療・看護への影響,(2)施設のライフライン,建築・医療設備の被害状況,(3)災害対策マニュアルとBCPの活用状況,(4)医療スタッフへの対応と健康管理について分析した。災害時の業務継続に向けた取り組むべき対策として,医療設備や地域性を考慮した「使える災害対策マニュアル・BCPの作成」,「災害に対する社会が持つ脆弱性を考慮した防災教育・訓練の実施」,「業務継続に伴う職員の健康管理対策および平常時の地域・広域施設との連携の強化」の重要性が示された。(著者抄録)

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    ISSN:0387-5911

    eISSN:1884-569X

  22. ウイルスポリメラーゼの不可逆阻害を目指した新規2′‐&βセレノ核酸アナログの創製

    村上努, 木村康明, 新美結士, 藤野真之, 片倉秀雄, 鈴木哲朗, 児玉栄一, 阿部洋

    日本エイズ学会誌 20 (4) 468-468 2018年11月20日

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  23. ウイルスポリメラーゼの不可逆阻害を目指した新規2'-&βセレノ核酸アナログの創製

    村上 努, 木村 康明, 新美 結士, 藤野 真之, 片倉 秀雄, 鈴木 哲朗, 児玉 栄一, 阿部 洋

    日本エイズ学会誌 20 (4) 468-468 2018年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  24. Gag-TSG101相互作用を標的とする新規HIV-1阻害薬の特徴(Characterization of novel HIV-1 inhibitors targeting Gag-TSG101 interaction)

    Lowela Siarot, Nopporn Chutiwitoonchai, 佐藤 洋隆, Hao Chang, 小谷 治, 横山 勝, 佐藤 裕徳, 藤野 真之, 村上 勉, 近藤 恭光, 本田 香り, 長田 裕之, 上田 一樹, 伊藤 嘉浩, 青野 俊裕, 児玉 栄一, 黒田 和道, 武井 正美, 間 陽子

    日本エイズ学会誌 20 (4) 522-522 2018年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  25. Gag-TSG101相互作用を標的とする新規HIV-1阻害薬の特徴(Characterization of novel HIV-1 inhibitors targeting Gag-TSG101 interaction)

    Lowela Siarot, Nopporn Chutiwitoonchai, 佐藤 洋隆, Hao Chang, 小谷 治, 横山 勝, 佐藤 裕徳, 藤野 真之, 村上 勉, 近藤 恭光, 本田 香り, 長田 裕之, 上田 一樹, 伊藤 嘉浩, 青野 俊裕, 児玉 栄一, 黒田 和道, 武井 正美, 間 陽子

    日本エイズ学会誌 20 (4) 522-522 2018年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  26. 生合成経路の再構築と再設計による糸状菌ジテルペノイドピロンライブラリーの構築と生物活性評価

    塚田健人, 塚田健人, 金子秋穂, 新木翔之, 河治久実, 児玉栄一, 倉石貴透, 村上一馬, 入江一浩, 平田尚也, 諫田泰成, 浅井禎吾

    メディシナルケミストリーシンポジウム講演要旨集 36th 48 2018年11月1日

    ISSN:0919-214X

  27. ウイルスポリメラーゼを標的とした不可逆阻害剤の開発

    新美結士, 片倉秀雄, 鈴木哲郎, 村上努, 児玉栄一, 木村康明, 阿部洋

    メディシナルケミストリーシンポジウム講演要旨集 36th 151 2018年11月1日

    ISSN:0919-214X

  28. 生合成経路の再構築と再設計による糸状菌ジテルペノイドピロンライブラリーの構築と生物活性評価

    塚田健人, 塚田健人, 金子秋穂, 新木翔之, 河治久実, 児玉栄一, 倉石貴透, 村上一馬, 入江一浩, 平田尚也, 諫田泰成, 浅井禎吾

    メディシナルケミストリーシンポジウム講演要旨集 36th 58 2018年11月1日

    ISSN:0919-214X

  29. 【これからの抗ウイルス療法】抗ウイルス薬の開発の将来展望

    児玉 栄一, 林 宏典, 臼井 恵美子

    臨床と微生物 45 (6) 685-688 2018年11月

    出版者・発行元:(株)近代出版

    ISSN:0910-7029

    詳細を見る 詳細を閉じる

    ウイルス迅速診断法の拡大に加えて、C型肝炎の完全治癒の達成、感染予防を目的とした抗ウイルス薬の投与という新たな局面からも抗ウイルス薬の可能性は拡大している。(著者抄録)

  30. 急性期病院で分離されたカルバペネム耐性腸内細菌科細菌(CRE)の解析

    牧野祐子, 金森肇, 遠藤史郎, 馬場啓聡, 大江千紘, 吉田眞紀子, 大島謙吾, 青柳哲史, 徳田浩一, 児玉栄一, 矢野寿一, 賀来満夫

    日本感染症学会東日本地方会学術集会・日本化学療法学会東日本支部総会合同学会プログラム・抄録集 67th-65th 136 2018年10月

  31. 大規模災害時の避難施設におけるウイルス性疾患対策 ワクチンと予防投与に期待されること

    児玉 栄一

    日本環境感染学会総会プログラム・抄録集 33回 96-96 2018年2月

    出版者・発行元:(一社)日本環境感染学会

  32. 創薬からアウトブレイクを制御する

    児玉 栄一

    東北医学雑誌 129 (2) 161-162 2017年12月

    出版者・発行元:東北医学会

    ISSN:0040-8700

  33. ゲンボイヤ配合錠(GEN;EVG/COBI/FTC/TAF)投与時の耐性発現症例の検討

    田沼 順子, 潟永 博之, 岡 慎一, 児玉 栄一, 中本 泰充, 池田 篤史, 小倉 直樹, Abram ME, Margot NA, Cox S., Callebaut C., Das M.

    日本エイズ学会誌 19 (4) 450-450 2017年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  34. 飛躍的に発展を見せる抗ウイルス薬 1.抗ウイルス薬の開発―今後のアプローチ―

    児玉栄一, 児玉栄一, 児玉栄一

    化学療法の領域 33 (1) 26‐31 2016年12月25日

    DOI: 10.20837/2201701026  

    ISSN:0913-2384

  35. 【飛躍的に発展を見せる抗ウイルス薬】抗ウイルス薬の開発 今後のアプローチ

    児玉 栄一

    化学療法の領域 33 (1) 26-31 2016年12月

    出版者・発行元:(株)医薬ジャーナル社

    ISSN:0913-2384

    詳細を見る 詳細を閉じる

    ペニシリンに代表される抗生物質は1940年台から本格的に臨床応用され,数多くの感染症患者を救ってきた。一方で,宿主代謝経路依存度の高いウイルスに対する治療薬開発は困難をきわめていたが,特異的抗ヘルペス薬Acyclovirの登場によって抗ウイルス薬開発は一気に加速し,現在はC型肝炎ウイルスをほとんどの症例で排除できるに至っている。今後の効率的な抗ウイルス薬開発に用いるスクリーニング法,治療対象となり得るウイルスについてワクチンとの棲み分けも含めて述べる。(著者抄録)

  36. 感染症治療の新戦略 新たな抗ウイルス薬の開発とその将来展望

    児玉 栄一

    感染症学雑誌 90 (臨増) 186-186 2016年3月

    出版者・発行元:(一社)日本感染症学会

    ISSN:0387-5911

  37. マウス着床前胚におけるレトロトランスポゾン抑制制御機構の解明

    畑中 勇輝, 井上 貴美子, 及川 真実, 上村 悟, 越後貫 成美, 児玉 栄一, 大川 恭行, 束田 裕一, 小倉 淳郎

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 88回・38回 [4T20L-09(3P0928)] 2015年12月

    出版者・発行元:(公社)日本生化学会

  38. 糖尿病啓発イベントからみえる糖尿病と歯周病の関連

    山田 紗智子, 由浪 有希子, 児玉 栄一, 伊藤 恵美, 小関 健由, 清元 秀康, 石井 正

    宮城県糖尿病看護研究会 10回 13-13 2014年6月

    出版者・発行元:宮城県糖尿病看護研究会

    ISSN:2187-2511

  39. 結核は一般病院でみる普通の病気になれるか? 県内一ヶ所の結核病棟を持つ病院の現状(宮城県の場合)

    内山 美寧, 平潟 洋一, 菅野 剛, 金森 肇, 児玉 栄一

    結核 89 (3) 298-298 2014年3月

    出版者・発行元:(一社)日本結核・非結核性抗酸菌症学会

    ISSN:0022-9776

    eISSN:1884-2410

  40. MAGI細胞による薬剤screeningにおいて酵素法がヒット化合物検出に優れる

    児玉 栄一

    日本エイズ学会誌 15 (4) 521-521 2013年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  41. ToMMoクリニカルフェローによる循環型地域支援の報告(第一期、第二期)

    阿部 倫明, 田中 淳一, 高山 真, 金村 政輝, 奈良 正之, 目時 弘仁, 関口 敦, 児玉 栄一, 坪井 明人, 瀧 靖之, 菅原 準一, 石井 正, 清元 秀泰, 八重樫 伸生

    日本医療・病院管理学会誌 50 (Suppl.) 272-272 2013年8月

    出版者・発行元:(一社)日本医療・病院管理学会

    ISSN:1882-594X

    eISSN:2185-422X

  42. 【抗ウイルス療法の現状と今後の展望】新しい抗ウイルス薬開発の考え方

    児玉 栄一, 宮本 総子

    臨床と微生物 40 (1) 009-013 2013年1月

    出版者・発行元:(株)近代出版

    ISSN:0910-7029

    詳細を見る 詳細を閉じる

    宿主代謝経路依存度の高いウイルスに対する治療薬開発は困難であったが、特異的抗ヘルペス薬acyclovirの同定後、抗ウイルス薬の概念は一変する。効率的な開発のためのスクリーニング法、unmet medical needs、特許戦略について述べる。(著者抄録)

  43. サハラ以南アフリカにおけるエイズ・結核研究ネットワーク構築の試み

    服部俊夫, 鈴木定彦, 山岡昇司, 井戸栄治, 一瀬休生, 仲宗根正, 久保亨, 臼澤基紀, 垣本和宏, 福本学, 児玉栄一

    日本国際保健医療学会学術大会プログラム・抄録集 27th 123 2012年11月2日

  44. EFdAおよびEdDAPに対する耐性変異が耐性度と複製能力に及ぼす影響

    宮本 総子, 満屋 裕明, 児玉 栄一

    日本エイズ学会誌 14 (4) 388-388 2012年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  45. Novel HIV-1 fusion inhibition peptides: Designing the next generation of drugs

    Fusako Miyamoto, Eiichi N Kodama

    Antiviral Chemistry and Chemotherapy 22 (4) 151-158 2012年

    DOI: 10.3851/IMP1930  

    ISSN:0956-3202

    詳細を見る 詳細を閉じる

    The development of over 20 antiretroviral drugs has led to efficient and successful suppression of HIV-1 replication. In addition to common viral targets, such as reverse transcriptase and protease, new targets have been recently exploited, including integrase, fusion and cellular CCR5. Hence, combination antiretroviral therapy is continually improved by the development of these new agents, especially for patients infected with drug-resistant HIV-1. In this review, we focused on fusion inhibitory peptides that have been developed since the first HIV-1 fusion inhibitor, enfuvirtide (T-20). T-20, approved for clinical use in 2003, is a polypeptide comprising 36 amino acids derived from the HIV-1 gp41 C-terminal heptad repeat and provides a novel treatment strategy for HIV-1 therapy. T-20 is able to suppress HIV-1 replication, including viruses resistant to reverse transcriptase or protease inhibitors. However, after prolonged T-20-containing treatment regimens, HIV-1 acquires resistance to T-20. Therefore, our laboratory and others have developed novel fusion inhibitors, termed next-generation fusion inhibitors, including electrostatically constrained, mutation introduced, and trimer-form peptides. © 2012 International Medical Press.

  46. 膜融合蛋白(F蛋白)を標的とした新規ペプチドによる亜急性硬化性全脳炎の新たな治療戦略

    渡部真裕, 橋本浩一, 阿部優作, 大原信一郎, 佐藤晶論, 川崎幸彦, 児玉栄一, 大石真也, 細矢光亮

    Neuroinfection 16 (2) 152 2011年10月21日

    ISSN:1348-2718

  47. がん遺伝子治療に向けた新しいPETレポーター/治療遺伝子の開発(Development of new PET reporter/ therapy gene for cancer gene therapy)

    渡邊 夕紀子, 児玉 栄一, 堀江 佐知子, 高地 崇, サックス・ニコラ, 柳下 陽子, 陳 鋭, 李 麗, 服部 俊夫, 森 士朗, 小玉 哲也

    日本癌学会総会記事 69回 366-366 2010年8月

    出版者・発行元:日本癌学会

    ISSN:0546-0476

  48. 新規抗HIV薬の開発 特集・抗ウイルス薬物療法の現状と今後の展望 (医薬ジャーナル)

    児玉栄一

    医薬ジャーナル 46 97-102 2010年4月

  49. 【抗ウイルス薬物療法の現状と今後の展望】抗HIV薬 新規抗HIV薬の開発

    児玉 栄一

    医薬ジャーナル 46 (2) 729-734 2010年2月

    出版者・発行元:(株)医薬ジャーナル社

    ISSN:0287-4741

    詳細を見る 詳細を閉じる

    抗HIV(ヒト免疫不全ウイルス)薬はこれまでに本邦でも20種類以上が認可され、その併用療法によって良好なHIV抑制が可能となった。しかし、一度宿主遺伝子中に組み込まれたHIVゲノムを取り除くことはできないため、長期にわたる治療継続、それに伴う副作用、服薬アドヒアランスの低下、薬剤耐性ウイルスの出現などの問題が依然解決されていない。これらの問題点を克服するため、逆転写酵素やプロテアーゼといった既存およびインテグラーゼや宿主レセプターであるCCR5のような新規標的に対する新薬の開発が進められている。本稿では今後臨床応用に向けて主に米国等で臨床治験に入っている新しい作用機序を持つ薬剤を中心にまとめてみた。(著者抄録)

  50. 新規抗HIV薬の開発 (特集 抗ウイルス薬物療法の現状と今後の展望) -- (抗HIV薬)

    児玉 栄一

    医薬ジャ-ナル 46 (2) 97-102 2010年2月

    出版者・発行元:医薬ジャ-ナル社

    ISSN:0287-4741

  51. The crystal structure of EFdA-resistant HIV-1 reverse transcriptase reveals structural changes in the polymerase active site

    B. Marchand, K. A. Kirby, D. Sietsema, E. N. Kodama, H. Mitsuya, M. A. Parniak, S. G. Sarafianos

    ANTIVIRAL THERAPY 15 A10-A10 2010年

    出版者・発行元:INT MEDICAL PRESS LTD

    ISSN:1359-6535

  52. The crystal structure of EFdA-resistant HIV-1 reverse transcriptase reveals structural changes in the polymerase active site

    B. Marchand, K. A. Kirby, D. Sietsema, E. N. Kodama, H. Mitsuya, M. A. Parmak, S. G. Sarafianos

    ANTIVIRAL THERAPY 15 (4) A10-A10 2010年

    出版者・発行元:INT MEDICAL PRESS LTD

    ISSN:1359-6535

  53. アルケン型ジペプチドイソスターの合成とケモカイン受容体CXCR4拮抗剤の構造活性相関研究への応用

    林亮子, 大石真也, 富田健嗣, 鳴海哲夫, 棚原憲子, 大野浩章, 内藤武志, 児玉栄一, 松岡雅雄, 藤井信孝

    メディシナルケミストリーシンポジウム講演要旨集 28th 116-117 2009年11月10日

    ISSN:0919-214X

  54. 抗ウイルス剤の作用点を中心に

    児玉 栄一, 服部 俊夫

    日本内科学会雑誌 98 (11) 2754-2761 2009年11月10日

    出版者・発行元:一般社団法人 日本内科学会

    DOI: 10.2169/naika.98.2754  

    ISSN:0021-5384

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    HIVは後天性免疫不全症候群(acquired immunodeficiency syndrome;AIDS)を引き起こすウイルスであり,また一方で遺伝子導入・治療のベクターとして用いられることから幅広い研究の対象となっている.抗レトロウイルス剤の作用やその耐性機序を知る上で複製機構の理解は必須である.本稿では現在臨床使用されている薬剤と治験中の薬剤がウイルス複製のどのステップを抑えているかを侵入,逆転写反応,組込み,転写,アッセンブリ,出芽の6ステップに分けて要約した.&lt;br&gt;

  55. HAARTによるオステオポンチンの誘導の意義に関する検討

    Haorile Chagan-Yasutan, 齋藤 弘樹, 芦野 有悟, 児玉 栄一, 服部 俊夫

    日本エイズ学会誌 11 (4) 575-575 2009年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  56. 【HIV感染症 流行の現状と最新の治療】HIV感染と増殖のメカニズム 抗ウイルス剤の作用点を中心に

    児玉 栄一, 服部 俊夫

    日本内科学会雑誌 98 (11) 2754-2761 2009年11月

    出版者・発行元:(一社)日本内科学会

    DOI: 10.2169/naika.98.2754  

    ISSN:0021-5384

    eISSN:1883-2083

  57. エンドキャップ抗HIV活性ペプチドSC35EKの合成

    梶原一美, 常盤礼, 渡辺健太郎, 大野浩章, 泉和樹, 児玉栄一, 松岡雅雄, 大石真也, 藤井信孝

    日本薬学会年会要旨集 129th (2) 186 2009年3月5日

    ISSN:0918-9823

  58. Identification of Novel HIV-1 Fusion Inhibitors by Template-Assisted Peptide Aldehyde Ligation

    TANAKA Michinori, WATANABE Kentaro, OHNO Hiroaki, IZUMI Kazuki, KODAMA Eiichi, MATSUOKA Masao, OISHI Shinya, FUJII Nobutaka

    Peptide science : proceedings of the ... Japanese Peptide Symposium 2008 361-362 2009年3月1日

    ISSN:1344-7661

  59. Structure Activity Relationship Study of the Helix-inducible Motifs in HIV Fusion Inhibitors

    WATANABE Kentaro, ITO Saori, OHNO Hiroaki, IZUMI Kazuki, KODAMA Eiichi, MATSUOKA Masao, OISHI Shinya, FUJII Nobutaka

    Peptide science : proceedings of the ... Japanese Peptide Symposium 2008 257-258 2009年3月1日

    ISSN:1344-7661

  60. Bioorganic Synthesis of End-capped HIV-1 Fusion Inhibitor SC35EK

    KAJIWARA Kazumi, TOKIWA Rei, WATANABE Kentaro, OHNO Hiroaki, IZUMI Kazuki, KODAMA Eiichi, MATSUOKA Masao, OISHI Shinya, FUJII Nobutaka

    Peptide science : proceedings of the ... Japanese Peptide Symposium 2008 203-204 2009年3月1日

    ISSN:1344-7661

  61. X-ray Crystallographic Study of the HIV-1 Fusion Inhibitor against the Drug-Resistant N43D Variant

    WATABE Tsuyoshi, OISHI Shinya, WATANABE Kentaro, OHNO Hiroaki, NAKANO Hiroaki, NAKATSU Toru, KATO Hiroaki, IZUMI Kazuki, KODAMA Eiichi, MATSUOKA Masao, FUJII Nobutaka

    Peptide science : proceedings of the ... Japanese Peptide Symposium 2008 229-232 2009年3月1日

    ISSN:1344-7661

  62. HIV-1 Rev-derived peptideはRevとCXCR4のdual-target inhibitorとして作用する

    嶋根 和毅, 児玉 栄一, 松岡 雅雄

    日本エイズ学会誌 10 (4) 539-539 2008年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  63. 逆転写酵素connectionとRNase H subdomainの多様性と薬剤感受性に及ぼす影響

    蜂谷 敦子, 嶋根 和毅, 児玉 栄一, 小泉 寛和, 潟永 博之, 松岡 雅雄, 滝口 雅文, 岡 慎一

    日本エイズ学会誌 10 (4) 422-422 2008年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  64. ヘリックス誘起モチーフを導入した抗HIVペプチドのデザインと合成

    渡辺健太郎, 大石真也, 伊藤紗織, 田中理紀, 西川祐樹, 渡部毅, 泉和樹, 坂上泰子, 児玉栄一, 松岡雅雄, 大野浩章, 藤井信孝

    日本薬学会年会要旨集 128th (2) 49 2008年3月5日

    ISSN:0918-9823

  65. Synthesis and Application of Novel Fluorescence-Labeled CXCR4 Antagonists

    MASUDA Ryo, OISHI Shinya, UEDA Satoshi, GOTO Yukiko, OHNO Hiroaki, EVANS Barry, PEIPER Stephen C., HIRASAWA Akira, TSUJIMOTO Gozoh, KODAMA Eiichi, MATSUOKA Masao, FUJII Nobutaka

    Peptide science : proceedings of the ... Japanese Peptide Symposium 2007 403-404 2008年3月1日

    ISSN:1344-7661

  66. Helix Inducible Motifs Affect Helicity and Bioactivity of Anti-HIV Peptides

    WATANABE Kentaro, ITO Saori, NISHIKAWA Hiroki, TANAKA Michinori, OISHI Shinya, OHNO Hiroaki, IZUMI Kazuki, KODAMA Eiichi, MATSUOKA Masao, FUJII Nobutaka

    Peptide science : proceedings of the ... Japanese Peptide Symposium 2007 311-312 2008年3月1日

    ISSN:1344-7661

  67. Chemical Virologyを基盤とする新興・再興ウイルス侵入阻害剤の開発研究

    藤井信孝, 大石真也, 西川裕樹, 渡部毅, 大野浩章, 氏家誠, 田口文広, 児玉英一, 松岡雅雄

    ケミカルバイオロジーシンポジウム発表要旨集 第4回 化学-生物融合領域創成の軌跡 理研シンポジウム 平成20年 41 2008年

  68. T‐20(Fuzeon)耐性HIV‐1変異株における6‐ヘリカルバンドル構造のX線構造解析

    渡部毅, 大石真也, 西川裕輝, 渡辺健太郎, 中野博明, 中津亨, 大野浩章, 加藤博章, 児玉栄一, 松岡雅雄, 藤井信孝

    日本化学会講演予稿集,88th,2,878 2008年

  69. Elvitegravir: An emerging HIV integrase inhibitor

    Kazuya Shimura, Eiichi Kodama

    Future HIV Therapy 2 (5) 411-418 2008年

    DOI: 10.2217/17469600.2.5.411  

    ISSN:1746-9600

    詳細を見る 詳細を閉じる

    Integration of the reverse transcribed HIV dsDNA into the host cell chromosome is critical for the subsequent production of progeny virions. In October 2007, the US FDA approved the first HIV-1 integrase inhibitor, raltegravir, as a therapeutic agent for treatment-experienced HIV-1-infected patients. Elvitegravir (GS-9137) is another HIV integrase inhibitor, which has a distinct chemical structure from raltegravir, and is currently being evaluated in HIV-1-infected patients. In Phase II clinical trials, elvitegravir combined with optimized background therapies significantly reduced the plasma HIV-1 viral load without serious adverse events up to 24 weeks. This article reviews the most recent available information on elvitegravir with respect to its clinical pharmacokinetics, pharmacodynamics and drug-resistance profile, and from the standpoint of extensive in vitro studies of its broad antiretroviral activity. © 2008 Future Medicine Ltd.

  70. インテグレース阻害剤に対する耐性HIVの誘導とその複製能の比較

    志村和也, 児玉栄一, 池田了, 松岡雅雄

    日本エイズ学会誌 9 (4) 405-405 2007年11月20日

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  71. 核酸系(NRTI)および非核酸系逆転写酵素阻害剤(NNRTI)に対する多剤耐性変異N348Iについて~その1/基礎的検討

    蜂谷敦子, 児玉栄一, 潟永博之, 松岡雅雄, 滝口雅文, 岡慎一

    日本エイズ学会誌 9 (4) 508-508 2007年11月20日

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  72. 核酸系(NRTI)および非核酸系逆転写酵素阻害剤(NNRTI)に対する多剤耐性変異N348Iについて~その2/臨床解析

    蜂谷敦子, 児玉栄一, 潟永博之, 松岡雅雄, 滝口雅文, 岡慎一

    日本エイズ学会誌 9 (4) 508-508 2007年11月20日

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  73. T‐20誘導体の抗HIV効果

    嶋根和毅, 泉和樹, 児玉栄一, 大石真也, 藤井信孝, 松岡雅雄

    日本エイズ学会誌 9 (4) 403 2007年11月20日

    ISSN:1344-9478

  74. EKコンセプトを利用した高活性HIV膜融合阻害剤の創製研究

    伊藤 紗織, 大石 真也, 西川 裕輝, 田中 理紀, 渡辺 健太郎, 泉 和樹, 児玉 栄一, 松岡 雅雄, 大野 浩章, 藤井 信孝

    日本薬学会年会要旨集 127年会 (4) 117-117 2007年3月

    出版者・発行元:(公社)日本薬学会

    ISSN:0918-9823

  75. Development of a novel fusion inhibitor against t-20-resistant HIV-1

    S. Oishi, S. Ito, H. Nishikawa, M. Tanaka, H. Ohno, A. Otaka, K. Izumi, E. Kodama, M. Matsuoka, N. Fujii

    BIOPOLYMERS 88 (4) 524-524 2007年

    出版者・発行元:JOHN WILEY & SONS INC

    ISSN:0006-3525

  76. HIV インチグレース阻害剤Elvitegravir (JTK-303/GS-9137) の抗ウイルス活性および耐性機序の解析 査読有り

    志村和也, 児玉栄一, 阪上泰子, 松崎裕児, 渡辺渡, 山高一修, 佐藤元秀, 加納光記, 池田了, 松岡雅雄

    第17 回抗ウイルス療法研究会、高松、2007 年5 月25 日-26 日 2007年

  77. C29 水溶性誘導体 SC29EK の抗HIV 効果 査読有り

    内藤武志, 泉和樹, 西川裕輝, 児玉栄一, 大石真也, 藤井信孝, 松岡雅雄

    第21 回日本エイズ学会学術集会・総会、広島、2007 年11月28-30 日 2007年

  78. T-20 耐性変異を利用した融 合阻害薬の開発 査読有り

    泉和樹, 児玉栄一, 志村和也, 大石真也, 藤井信孝, 松岡雅雄

    第21回日本エイズ学会学術集会・総会、広島、2007 年11月28-30 日 2007年

  79. T-20 耐性HIV-1 に対して有効な融合阻害薬の開発 査読有り

    泉和樹, 西川裕輝, 伊藤紗織, 児玉栄一, 志村和也, 大石真也, 藤井信孝, 松岡雅雄

    第17 回抗ウイルス療法研究会、香川、 2007 年5 月25-26 日 2007年

  80. NRTIを含む治療中に誘導された新しいネビラピン(NVP)耐性変異

    蜂谷敦子, 潟永博之, 児玉栄一, 松岡雅雄, 滝口雅文, 岡慎一

    日本エイズ学会誌 8 (4) 411-411 2006年11月20日

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  81. EKコンセプトを利用した高活性HIV膜融合阻害剤の創製研究

    伊藤紗織, 大石真也, 西川裕輝, 田中理紀, 泉和樹, 児玉栄一, 松岡雅雄, 大野浩章, 藤井信孝

    メディシナルケミストリーシンポジウム講演要旨集 25th 62-63 2006年11月10日

    ISSN:0919-214X

  82. SARSコロナウイルススパイク(S)蛋白質のHeptad Repeat由来Peptide(HR‐p)は細胞表面からのウイルス侵入を効果的に抑制する

    氏家誠, 西川裕輝, 大高章, 山本直樹, 山本典生, 松岡雅雄, 児玉栄一, 藤井信孝, 田口文広

    日本ウイルス学会学術集会プログラム・抄録集 54th 168 2006年11月1日

  83. 2'-Deoxy-4'-C-ethynyl-2-fluoroadenosine(E2 FdA)の細胞内代謝とDNAポリメラーゼに対する阻害作用の検討

    中田 浩智, 天野 将之, こう 康博, 満屋 裕明, 児玉 栄一, Yang Guangwei, 向後 悟, 早川 弘之, 大類 洋, 松岡 雅雄, Chen Yung-Chi

    感染症学雑誌 80 (6) 803-803 2006年11月

    出版者・発行元:(一社)日本感染症学会

    ISSN:0387-5911

  84. サイエンスが直面する難題を有機化学の基本でブレークスルーするPartII,画期的抗HIVヌクレオシドの創製

    大類洋, 向後悟, 早川弘之, 児玉栄一, 松岡雅雄, 満屋裕明

    天然有機化合物討論会講演要旨集 48th (48) 547-552 2006年9月15日

    出版者・発行元:天然有機化合物討論会

    DOI: 10.24496/tennenyuki.48.0_547  

  85. サイエンス(人類)が直面する難題を有機化学でブレークスルーしよう!―エイズとB型肝炎の夢の治療薬の開発!?―

    大類洋, 向後悟, 早川弘之, 児玉栄一, 松岡雅雄, 満屋裕明

    万有生命科学振興国際交流財団仙台シンポジウム 17th 61 2006年6月24日

  86. HIV検査体制の構築に関する研究 B. HIV検査陽性者(感染者)のケアーのためより効果的なHIVのフォローアップ検査体制を構築するための研究 B‐4. 新規感染者および非サブタイプBを対象にした薬剤耐性試験と感受性試験のデータの構築について

    蜂谷敦子, 根岸ふじ江, 潟永博之, 木村哲, 岡慎一, 児玉栄一, 松岡雅雄

    HIV検査体制の構築に関する研究 平成15-17年度 総合研究報告書 256-262 2006年

  87. HIV検査体制の構築に関する研究 B. HIV検査陽性者(感染者)のケアーのためより効果的なHIVのフォローアップ検査体制を構築するための研究 B‐4. 非サブタイプB HIVにおける薬剤耐性試験と感受性試験のデータの構築について

    蜂谷敦子, 根岸ふじ江, 児玉栄一, 松岡雅雄, 岡慎一, 木村哲

    HIV検査体制の構築に関する研究 平成17年度研究報告書 242-246 2006年

  88. In Vitro Antiviral Activity and Resistance Profile of a Novel HIV Integrase Inhibitor JTK-303/GS-9137. 査読有り

    Kodama E, Shimura K, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Sato M, Kano M, Ikeda S, Matsuoka M

    46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, Sep 27-30, 2006. 2006年

  89. 新規HIV インチグレース阻害剤JTK-303/GS-9137の抗HIV 活性および耐匪機序の解析 査読有り

    志村和也, 児玉栄一, 池田了, 松岡雅雄

    第20 回日本エイズ学会学術集会・総会、東京、2006年11月30 日-12 月2日 2006年

  90. 膜融合阻害ペプチドN36 に対する耐匪HIVの誘導と解析 査読有り

    泉和樹, 児玉栄一, 藤井信孝, 松岡雅雄

    第9 回白馬シンポジウム、京都、2006 年10 月12-13 日 2006年

  91. 強力な抗HIV活性を示す2’‐Deoxy4’‐C‐ethynyl‐2‐haloadenosine誘導体の設計と合成

    向後悟, 岩井優子, 芦田則之, 早川弘之, 川本敦司, 児玉栄一, 松岡雅雄, 満屋裕明, 大類洋

    メディシナルケミストリーシンポジウム講演要旨集 24th 56-57 2005年11月10日

    ISSN:0919-214X

  92. 融合阻害剤 T-20(Fuzeon)に対 する耐性HIV の解析 査読有り

    上野真理子, 梶原慶子, 志村和也, 児玉栄一, 松岡雅雄

    第19 回日本エイズ学会学術集会・総会、熊本、2005 年12 月 1-3 日 7 (4) 360-360 2005年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  93. 核酸系逆転写酵素阻害剤 2'-Deoxy-4'-C-ethynyl-2-fluoro-adenosine(E2FdA)の細胞内動態の検討

    中田 浩智, 天野 将之, こう 康博, 児玉 栄一, Yang Guangwei, 向後 悟, 早川 弘之, 大類 洋, 松岡 雅雄, Chen Yun-Chi, 満屋 裕明

    日本エイズ学会誌 7 (4) 423-423 2005年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  94. 核酸系逆転写酵素阻害剤4’ -ethynyl-2-halo-deoxyadenosine 誘導体の耐性HIV 複製阻害活性の検討 査読有り

    川本敦司, 児玉栄一, 大類洋, 満屋裕明, 松岡雅雄

    第19 回日本エ イズ学会学術集会・総会、熊本、2005 年12 月1-3 日 7 (4) 423-423 2005年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  95. 水溶性C34誘導体の抗HIV効果

    児玉 栄一, 梶原 慶子, 大高 章, 藤井 信孝, 松岡 雅雄

    日本エイズ学会誌 7 (4) 418-418 2005年11月

    出版者・発行元:日本エイズ学会

    ISSN:1344-9478

  96. アマンタジン誘導体の抗HIV活性

    千葉卓男, 児玉栄一, 松岡雅雄

    化学系学協会東北大会プログラムおよび講演予稿集 2005 291 2005年9月15日

  97. 広いスペクトラムのHIVに著効を示す低毒性ヌクレオシド誘導体の開発:特に3’‐OHの生物活性に対する役割について

    大類洋, 向後悟, 向後悟, 北濃健司, 芦田則之, 早川弘之, 児玉栄一, 松岡雅雄, 満屋裕明

    日本農芸化学会大会講演要旨集 2005 181 2005年3月5日

  98. 4 '-C-ethynyl-2 '-deoxy-2-fluoroadenosine, a nucleoside derivative potent against HIV-1 with no acute mouse toxicity: Highlights of the role of 3 '-OH for biological activity

    H Ohrui, S Kohgo, K Kitano, N Ashida, H Hayakawa, E Kodama, M Matsuoka, H Mitsuya

    ANTIVIRAL RESEARCH 65 (3) A42-A42 2005年3月

    出版者・発行元:ELSEVIER SCIENCE BV

    ISSN:0166-3542

  99. HIV-1 Acquires Resistance to New NNRTI, Thiazol Derivatives, through Steric Hindrance with Multiple Mutations. 査読有り

    Kodama E, Masuda N, Orita M, Yamamoto O, Fujii M, Kageyama S, Ohta M, Hatta T, Inoue H, Suzuki H, Sudo K, Shimizu Y, Matsuoka M

    12th conference on retroviruses and opportunistic infections. Boston, MA, Feb 22-25, 2005. 2005年

  100. MTT 法を用いたCXCR4 およびCCR5 トロピックHIV-1 に対する薬剤感受性試験法 査読有り

    梶原慶子, 児玉栄一, 松岡雅雄

    第19 回日本エイズ学会学術集会・総会、熊本、2005 年 12 月1-3 日 2005年

  101. ELISAを応用した迅速なHIV‐fusion inhibitor screening法の確立

    児玉栄一, 榊原綾子, 大高章, 藤井信孝, 松岡雅雄

    日本エイズ学会誌 6 (4) 514-514 2004年11月20日

    出版者・発行元:日本エイズ学会

    ISSN:1344-9478

  102. HIV侵入の動的超分子機構を標的とした膜融合阻害剤の創製

    西川裕輝, 大高章, 玉村啓和, 藤井信孝, 松岡雅雄, 児玉栄一

    日本薬学会年会要旨集 124th (2) 44-44 2004年3月5日

    出版者・発行元:(公社)日本薬学会

    ISSN:0918-9823

  103. A GENERAL STRATEGY FOR DEVELOPMENT OF ANTI-VIRUS PEPTIDES BASED ON X-EE-XX-KK CONCEPT FOR THE ALPHA-HELICAL ENV SEQUENCE: PRACTICE IN AIDS AND SARS

    A. Otaka, N. Yamamoto, E. Kodama, H. Tamamura, M. Matsuoka, N. Yamamoto, N. Fujii

    JOURNAL OF PEPTIDE SCIENCE 10 112-112 2004年

    出版者・発行元:JOHN WILEY & SONS LTD

    ISSN:1075-2617

  104. Potential of 4′-C-substituted nucleosides for the treatment of HIV-1

    Hiroyuki Hayakawa, Satoru Kohgo, Kenji Kitano, Noriyuki Ashida, Eiichi Kodama, Hiroaki Mitsuya, Hiroshi Ohrui

    Antiviral Chemistry and Chemotherapy 15 (4) 169-187 2004年

    出版者・発行元:International Medical Press Ltd

    DOI: 10.1177/095632020401500401  

    ISSN:0956-3202

    詳細を見る 詳細を閉じる

    Extensive efforts have been made to identify nucleoside reverse transcriptase inhibitors (NRTIs). Eight NRTIs have now been approved for clinical use however, variants of HIV-1 resistant to these antiviral agents have emerged in patients even when they are treated with combinations [highly active antiretroviral therapy (HAART)]. Thus, the development of novel compounds that are active against drug-resistant HIV-1 variants and that prevent or delay the emergence of resistant HIV-1 variants is urgently needed. Previously, 4′-C-substituted nucleosides (4′-SNs) were designed as new types of NRTIs. They were synthesized and examined as potential therapeutic agents against HIV infection. Among them, several 4′-substituted-2′- deoxynucleosides (4′-SdNs), especially those that bear an ethynyl group, were shown to be active against various laboratory and clinical HIV-1 strains including known drug-resistant variants. These results were recently reported by our collaborators. In this review, we summarize the design, synthesis and demonstrations of the anti-HIV activity of 4′-SNs, and then consider 4′-SNs as potential therapeutic agents for HIV-1.

  105. Peptide fusion inhibitor C34に対する耐性機序の解析

    児玉栄一, 大高章, 藤井信孝, 松岡雅雄

    日本エイズ学会誌 5 (4) 403-403 2003年11月20日

    出版者・発行元:日本エイズ学会

    ISSN:1344-9478

  106. C34誘導体SC34およびSC34EKはfusion inhibitor耐性ウイルスに効果を示す

    行木大輔, 児玉栄一, 大高章, 藤井信孝, 松岡雅雄

    日本エイズ学会誌 5 (4) 324 2003年11月20日

    ISSN:1344-9478

  107. Oligoarginine-mediated Delivery of Bioactive Peptides into Living cells

    FUTAKI Shiroh, NAKASE Ikuhiko, NIWA Miki, SUZUKI Tomoki, NAMEKI Daisuke, KODAMA Ei-ichi, MATSUOKA Masao, SUGIURA Yukio

    Peptide science : proceedings of the ... Japanese Peptide Symposium 2002 73-76 2003年2月1日

    ISSN:1344-7661

  108. HIV感染に関与するヘリックスバンドルのX線結晶構造決定と熱力学的解析

    中村昇太, 中野博明, 内山進, 大高章, 藤井信孝, 松岡雅雄, 児玉栄一, 山県ゆり子, 小林祐次

    生化学 74 (11) 1405-1405 2002年11月25日

    出版者・発行元:(公社)日本生化学会

    ISSN:0037-1017

  109. 多剤耐性HIVにも有効な4′位置換プリンヌクレオシド 天然ヌクレオシドからの合成とその評価

    北濃健司, 向後悟, 坂田紳二, 早川弘之, 行木大輔, 児玉栄一, 松岡雅雄, 満屋裕明, 大類洋

    メディシナルケミストリーシンポジウム・日本薬学会医薬化学部会年会講演要旨集 22nd-11th 74-76 2002年11月5日

    ISSN:0919-214X

  110. HIV-1 gp41C末端由来ペプチドC34による耐性化機序の解明

    行木 大輔, 児玉 栄一, 松岡 雅雄

    日本エイズ学会誌 4 (4) 294-294 2002年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  111. 新規感染患者から検出された新たなネビラピン(NVP)耐性変異について

    蜂谷 敦子, 児玉 栄一, 松岡 佐織, 土屋 亮人, 立川 夏夫, 安岡 彰, 満屋 裕明, 松岡 雅雄, 木村 哲, 岡 慎一

    日本エイズ学会誌 4 (4) 296-296 2002年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  112. α‐helix形成モチーフ導入型HIV‐1‐細胞膜融合阻害剤の創製

    大高章, 中村美紀, 児玉栄一, 中村昇太, 中野宏明, 玉村啓和, 小林祐次, 松岡雅雄, 藤井信孝

    反応と合成の進歩シンポジウム講演要旨集 28th 130-131 2002年10月15日

    ISSN:0919-2123

  113. 【HIV/AIDS研究の進歩】 抗HIV薬・ワクチンの開発研究の進歩 新しい逆転写酵素阻害剤 (日本臨床)

    児玉栄一

    日本臨床 60 (4) 775-779 2002年4月

  114. HIV感染初期過程に関わる6‐helical‐bundle構造を標的とした高活性膜融合阻害剤(SC34)の創出とその応用研究

    中村美紀, 大高章, 児玉栄一, 松岡雅雄, 内山進, 中村昇太, 小林祐次, 玉村啓和, 藤井信孝

    日本薬学会年会要旨集 122nd (2) 183-183 2002年3月5日

    出版者・発行元:(公社)日本薬学会

    ISSN:0918-9823

  115. HIV感染に関与するヘリックスバンドルの熱力学的解析

    中村昇太, 中野博明, 内山進, 大久保忠恭, 松岡雅雄, 児玉栄一, 中村美紀, 藤井信孝, 小林祐次

    日本薬学会年会要旨集 122nd (3) 23-23 2002年3月5日

    出版者・発行元:(公社)日本薬学会

    ISSN:0918-9823

  116. Arginine‐richペプチドを用いたRNase S複合体の細胞内導入

    二木史朗, 中瀬生彦, 鈴木智樹, 丹羽美紀, 行木大輔, 児玉栄一, 松岡雅雄, 杉浦幸雄

    日本薬学会年会要旨集 122nd (2) 177-177 2002年3月5日

    出版者・発行元:(公社)日本薬学会

    ISSN:0918-9823

  117. 新規の核酸系逆転写酵素阻害剤(4′‐ethynyl nucleoside)に対するHIV‐1の耐性化機序の解析

    児玉栄一, 満屋裕明, 松岡雅雄

    日本エイズ学会誌 3 (4) 388-388 2001年11月20日

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  118. HIV‐1 gp41N末端由来のペプチドN36による耐性化機序の解明

    行木大輔, 児玉栄一, 松岡雅雄

    日本エイズ学会誌 3 (4) 389-389 2001年11月20日

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  119. 抗HIVペプチドN36耐性株から誘導されたC34KQとN36の複合体のX線結晶解析

    中村昇太, 中野博明, 内山進, 大高章, 藤井信孝, 松岡雅雄, 児玉栄一, 山県ゆり子, 小林祐次

    日本生物物理学会年会講演予稿集 39th 2001年

    ISSN:0582-4052

  120. 1P005抗HIVペプチドN36耐性株から誘導されたC34KQとN36の複合体のX線結晶解析

    中村 昇太, 中野 博明, 内山 進, 大高 章, 中村 美紀, 藤井 信孝, 松岡 雅雄, 児玉 栄一, 山縣 ゆり子, 大久保 忠恭, 小林 祐次

    生物物理 41 (0) S34 2001年

    出版者・発行元:一般社団法人 日本生物物理学会

    DOI: 10.2142/biophys.41.S34_1  

  121. 学会印象記 8th Conference on Retroviruses and Opportunistic Infections印象記

    児玉 栄一

    日本エイズ学会誌 3 (3) 175-177 2001年

    出版者・発行元:日本エイズ学会

    DOI: 10.11391/aidsr1999.3.175  

    ISSN:1344-9478

  122. 4'-Ethynyl nucleosides 多剤耐性HIVに著効する新規nucleoside reverse transcriptase inhibitor(NRTI)

    児玉 栄一, 大類 洋, 茂田 士郎, 満屋 裕明, 松岡 雅雄

    日本エイズ学会誌 2 (4) 456-456 2000年11月

    出版者・発行元:(一社)日本エイズ学会

    ISSN:1344-9478

  123. 抗ウイルス薬の進歩 (日本医事新報)

    茂田士郎, 児玉栄一, 橋本浩一

    日本医事新報 (3730) 26-30 1995年10月

︎全件表示 ︎最初の5件までを表示

書籍等出版物 2

  1. Revを標的とした新規抗HIV療法の確立

    児玉 栄一(ウィルス学, 京都大学ウイルス研究所

    [児玉栄一] 2007年

  2. ウイルス感染症との闘い

    茂田士郎, 満屋裕明, ds, 児玉栄一, 松岡雅雄, 満屋裕明

    医薬ジャーナル社 2001年7月

講演・口頭発表等 22

  1. 4'-Ethynyl-核酸誘導体に対するHIV-1及びHIV-2の耐性機序

    宮本総子, 服部俊夫, 児玉栄一

    第25回日本エイズ学会学術集会・総会 2011年11月30日

  2. HIV-1 Reverse Transcriptase (RT) Polymorphism 172K Suppresses the Effect of Clinically Relevant Drug Resistance Mutations to Both Nucleoside and Nonnucleoside RT Inhibitors. 国際会議

    Atsuko Hachiya, Bruno Marchand, Karen A. Kirby, Eleftherios Michailidis, Xiongying Tu, Yee Tsuey Ong, Daniel T. Griffin, Matthew M. Schuckmann, Junko Tanuma, Shinichi Oka, Kamalendra Singh, Eiichi N. Kodama, Stefan G. Sarafianos

    12th Annual Symposium on Antiviral Drug Resistance 2011年11月6日

  3. Development of HIV-1 fusion inhibitors active ,to enfuvirtide (T-20) resistant variants 国際会議

    児玉栄一

    U.S-Japan cooperative Medical Sciences Panel 2010年12月8日

  4. HAART施行中の薬剤副作用に対するRaltegravirへの薬剤変更を行った10例

    齋藤弘樹, 芦野有悟, 児玉栄一, 服部俊夫

    第24回日本エイズ学会 2010年11月24日

  5. 当院におけるHAART施行中の手術症例

    芦野有悟, 齋藤弘樹, 児玉栄一, 服部俊夫

    第24回日本エイズ学会 2010年11月24日

  6. カテキン2量体procyanidin B1はHCV複製を抑制する

    児玉栄一, Li Schenwei, 服部俊夫

    第20回日本抗ウイルス療法研究会 2010年5月19日

  7. Retroviral Integrase Inhibitor,elvitegravir(JK-303/GS9137)Mechanism of action and resistance.

    児玉栄一

    International Symposium on AIDS & TUBERCULOSIS 2010年1月13日

  8. Procyanidin B-1 suppresses HCV replication

    Shenwei Li, 児玉栄一, Zhang Jing, 服部俊夫

    第57回ウイルス学会学術集会 2009年10月25日

  9. Drugs design for resistant HIV

    Kodama E

    Kumamoto AIDS Seminar Satellite Symposium 2009年9月30日

  10. Retroviral integrase inhibitor, elvitegravir(JTK-303/GS9137) 国際会議

    児玉栄一

    the Korea-Japan basic scientific cooperation program 2007年12月5日

  11. A Novel Mutations,N3481 in HIV-1 Reverse transcriptase Induced by NRTI Treatment,Confers Nevirapine Resistance. 国際会議

    Hachiya A, Kodama E, Sarafianos SG, Schuckmann M, Matsuoka M, Takiguchi, Gatanaga H, Oka S

    The 14th Conference on Retroviruses and Opportunistic Infections. 2007年2月25日

  12. In Vitro Antiviral Activity and Resistance profile of a Novel HIV Integrase Inhibitor JTK-303/GS-9137 国際会議

    Kodama E, SHimura K, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Sato M, Kano M, Ikeda S, Matsuoka M

    The 46th Interscience Conference on Antimicrobial Agents and Chemotherapy 2006年9月27日

  13. Mutations Conferring Resistance to HIV-1 Fusion Unhibitors are Restricted by gp41 and rev responsive Element Functions.

    Kodama E, Mabuchi N, Otaka A, Ohno M, Fujii M, Matsuoka M

    The 7th International Congress on AIDS in Asia and the pacific. 2005年7月1日

  14. HIV-1 Acquires Resistance to New NNRT1,Thiazol Derivatives,through Steric hindrance with Multiple Mutations. 国際会議

    Kodama E, masuda N, Orita M, Yamamoto O, Fujii M, Kageyama S, Ohta M, Hatta T, Inoue H, Suzuki H, Sudo K, Shimizu Y, Matsuoka M

    The 12th Conference on Retroviruses and Opportunistic Infections. 2005年2月22日

  15. HIV-1 fusion inhibitor-resistance and development of the new inhibitors.

    Kodama E

    The Japan-Korea Basic Scientific Cooperation Program 2004年11月17日

  16. Resistant mutations to HIV-1 fusion inhibitors are restricted by gp41 and Rev responsive element functioins. 国際会議

    Kodama E, Ikeuchi M, Mabuchi N, Otaka A, Ohno M, Fujii N, Matsuoka M

    The11th Conference on Retroviruses and Opportunistic Infections. 2004年2月8日

  17. Development of a novel fusion inhibitor,SC34EK 国際会議

    Kodama E, Nameki D, Ikeuchi M, Otaka A, Tamamura H, Fujii N, Matsuoka M

    The10th Conference on Retroviruses and Opportunistic Infections. 2003年2月10日

  18. Generation of HIV variants resistant to 4'-ethynyl-2'-deoxynucleosides. 国際会議

    Kodama E, ikeuchi M, Matsuoka M, mitsuya M

    The 9th Conference on Retroviruses and Opportunisyic Infections. 2002年2月24日

  19. 4'-Ethynyl nucleoside analogs 国際会議

    Kodama E, Ohrui H, Gatanaga H, Shigeta S, matsuoka M, Miysuya H

    The 8th Conference on Retroviruses and Opportunistic Infections. 2001年2月4日

  20. 4'-Ethynyl nucleoside analogs

    kodama E, Ohrui H, Gatanaga H, Sigeta S, Matsuoka M, mitsuya H

    The 8th International Antiviral Symposium and Workshop 2000年11月19日

  21. In vitro Anti-HIV-1activity of and virsl drug resistance profiles against phosphoralaninate diesters of Z-and E-methylene cyclopropene analogues. 国際会議

    Yoshimura K, uchida H, Kodama E, maeda Y, Feldman R, Qiu Y-L, Zemlicka j, mitsuya H

    The 5th Conference on Retroviruses and Opportunistic Infections. 1998年2月1日

  22. Analysis of mutation in the thymidine kinase gene of varicella zoster virus associated with resistance to5-iodo-2'-deoxyuridine and 5-bromo-2'-deoxyuridine. 国際会議

    Kodama E, Mori S, Shigeta S

    The 8th International Conference on Antiviral Reserch. 1995年4月23日

︎全件表示 ︎最初の5件までを表示

産業財産権 12

  1. 4’−C−置換−2−ハロアデノシン誘導体

    向後 悟, 大類 洋, 児玉 栄一, 松岡 雅雄, 満屋 裕明

    特許第5213194号

    産業財産権の種類: 特許権

  2. 修飾ペプチド及びその製造方法

    藤井 信孝, 松岡 雅雄, 児玉 栄一, 大石 真也, 田中 理紀, 秦 洋二, 堤 浩子, 梶原 一美, 常磐 礼

    産業財産権の種類: 特許権

  3. エプスタイン・バールウイルス関連疾患に対する薬剤およびそのスクリーニング法

    児玉 栄一

    産業財産権の種類: 特許権

  4. 4’−C−エチニルヌクレオシド化合物

    大類 洋, 向後 悟, 児玉 栄一, 松岡 雅雄, 満屋 裕明

    産業財産権の種類: 特許権

  5. 抗HIV剤

    藤井 信孝, 大石 真也, 松岡 雅雄, 児玉 栄一

    産業財産権の種類: 特許権

  6. 抗HIV剤

    藤井 信孝, 大石 真也, 松岡 雅雄, 児玉 栄一

    産業財産権の種類: 特許権

  7. N36結合ペプチドの製造方法

    堤 浩子, 石田 博樹, 久田 博元, 水本 真紀子, 秦 洋二, 藤井 信孝, 松岡 雅雄, 児玉 栄一, 大石 真也

    産業財産権の種類: 特許権

  8. 4’−C−置換−2−ハロアデノシン誘導体

    向後 悟, 大類 洋, 児玉 栄一, 松岡 雅雄, 満屋 裕明

    産業財産権の種類: 特許権

  9. 4’−C−シアノ−2’−デオキシプリンヌクレオシド

    向後 悟, 山田 浩平, 坂田 紳二, 大類 洋, 児玉 栄一

    産業財産権の種類: 特許権

  10. 4’−C−エチニルプリンヌクレオシド化合物

    大類 洋, 向後 悟, 児玉 栄一, 松岡 雅雄, 満屋 裕明

    特許第4076114号

    産業財産権の種類: 特許権

  11. 4’−C−エチニルピリミジンヌクレオシド化合物

    大類 洋, 向後 悟, 児玉 栄一, 茂田 士郎, 満屋 裕明

    特許第4039790号

    産業財産権の種類: 特許権

  12. エプスタイン・バールウイルス関連疾患に対する薬剤およびそのスクリーニング法

    児玉 栄一, 松岡 雅雄, 芦田 則之

    特許第5326173号

    産業財産権の種類: 特許権

︎全件表示 ︎最初の5件までを表示

共同研究・競争的資金等の研究課題 17

  1. 呼吸器ウイルス感染症における重症化抑制に関する研究

    菊地 章子, 山谷 睦雄, 児玉 栄一, 高山 真, 西村 秀一

    2023年4月1日 ~ 2028年3月31日

  2. 新規免疫抑制分子Plet-1の機能解析と革新的なARDS治療薬の開発

    笠松 純, 佐藤 光, 児玉 栄一

    2022年4月1日 ~ 2025年3月31日

  3. コロナウイルス制圧のための新規膜融合阻害ペプチドの創出と合理的な設計法の確立

    児玉 栄一, 大石 真也

    2021年7月9日 ~ 2024年3月31日

    詳細を見る 詳細を閉じる

    本研究は、ウイルス膜融合をモデルとしてヘリックス相互作用を阻害することによって効率的で汎用性の高いタンパク機能阻害剤の開発方法を提案することを目的にしている。方法論の確立に加えて迅速な社会実装を踏まえ、昨今のパンデミックをおこした新型コロナウイルスをモデルとしている。本ウイルスの侵入機序はClass I膜融合である。この膜融合にスパイクタンパクC末端側に位置するウイルスエンベロープ貫通ドメインを有するウイルス融合タンパク(FP)が重要な役割を果たす。このFPには特徴的な2つのヘリックス構造があり、このヘリックス相互作用によるFPの構造変化が侵入に大切である。この構造変化阻害のためFPを標的としたペプチド設計法とin vitro 耐性誘導を組み合わせ、1)設計-2)評価-3)耐性ウイルス誘導-4)耐性機序の解明-5)耐性機序を利用したペプチド創製(最終段階の5)は1)の設計につながる)といった 4 工程を繰り返すことにより、より強力で薬剤耐性を生じにくい阻害剤を効果的にかつ短期間に開発することを目指す。本年度は、効率的な抗ウイルス活性の評価方法として非感染系で迅速にハイスループットが期待できる独自のELISA法を開発した。さらに培養細胞と感染性ウイルスを用いる従来評価法を応用し、より安全で短期間にできるMTT色素法を組み合わせた培養評価系も確立した。これらを駆使し、ウイルス感染を抑制しうる重要なアミノ酸配列の同定、複数の候補ペプチド配列を同定している。また、新たなウイルスパネルも構築しつつある。本年度の進捗は順調である。

  4. 細胞治療を指向した機能性エクソソーム分泌細胞内包ゲルの開発

    中瀬 生彦, 萩原 将也, 上田 真史, 児玉 栄一

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research

    研究種目:Grant-in-Aid for Challenging Research (Pioneering)

    研究機関:Osaka Prefecture University

    2019年6月28日 ~ 2022年3月31日

    詳細を見る 詳細を閉じる

    細胞分泌小胞であるエクソソーム(直径が約30-200 nm)は、生体を構成するほとんど全ての細胞から分泌され、血液や尿などの体液中に大量に含まれる。エクソソームの内部には、microRNAや酵素等の生理活性分子が内包され、分泌されたエクソソームは、周辺の細胞によって取り込まれ、エクソソーム内包分子によって細胞機能に影響を与える。加えてエクソソームは、薬物送達における観点(免疫制御、細胞機能制御分子の天然・人工内包、膜タンパク質の精密構築、血液脳関門の通過等)において高い優位性を有し、次世代型の薬物運搬体として大きく期待されている。一方で、繰り返し投与の必要性やエクソソーム単離効率の低さといった問題点は未解決のままである。本研究課題では、細胞特異的に薬剤送達が可能な機能性エクソソームを分泌可能な細胞内包ゲルシステムの確立を目的とする。研究開発目的として、治療や診断に役立つ機能性エクソソームを分泌する細胞をゲルに内包することで、エクソソームのみがゲルから分泌されるシステムであり、本技術を基盤とした細胞治療法の構築を目指す。令和元年度において、アガロースゲルを用いて、エクソソームは通過するが、その母細胞は通過できないように内包した細胞封入体を作製し、その細胞保持能やエクソソーム分泌性、周辺細胞へのエクソソーム移行性等を中心に詳細な検討を行なった。詳細を「現在までの進捗状況」に示すが、ゲル内包細胞の比較的高い細胞生存率、及び、細胞内包ゲルからの性状を維持したエクソソーム分泌と、分泌後に周辺のがん細胞にエクソソームが効果的に取り込まれることを確認した。今後、細胞治療に向けた基盤技術のさらなる最適化が必要だが、現段階において根幹となる手法構築の確立に成功している。

  5. ストレス応答生合成と化学修飾を融合した多様性天然物による難治性疾患治療薬の開発

    児玉 栄一, 林 宏典, 浅井 禎吾, 菊地 晴久

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research

    研究種目:Grant-in-Aid for Scientific Research (B)

    研究機関:Tohoku University

    2019年4月1日 ~ 2022年3月31日

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    本研究は、全く新しい骨格を持つ化合物ライブラリーと革新的スクリーニング法を開発、それらを駆使し既存薬と一線を画す新たな作用機序を有するヒット化合物の網羅的探索を目的とした。令和元年度の主な3つの研究成果概要を次に示す。(1) 糸状菌二次代謝産物の生合成経路の改変・再設計による新規擬天然化合物ライブラリーを構築した。糸状菌ゲノム解析の進展により糸状菌が合成する二次代謝産物の設計図が明らかとなった。令和元年度は、ゲノム情報を基に外来遺伝子導入による糸状菌二次代謝産物の生合成経路の改変・再設計を行った。得られた新規化合物の抗ウイルス活性を測定、HIV-1に対してウイルス抑制効果を発揮する化合物の同定に成功した。(2) アデノウイルス (AdV) に対する抗ウイルス効果を迅速・簡便に測定する実験系を構築した [Antivir Chem Chemother. 2020]。結膜細胞に感染したAdVは流行性角結膜炎 (EKC) の原因となる。これまで結膜細胞感染AdVに対する抗ウイルス活性の測定には、ウサギの眼球を使用していたが本手法ではヒト結膜細胞由来の実験用細胞株、CRL11516細胞を用いており従来の手法に比して簡便・迅速かつ高いコストパフォーマンスを実現しただけでなく動物愛護の観点からも有用な成果となった (論文作成中)。(3) 薬剤耐性菌 (AMR) に有効で既存の抗菌薬と異なる作用機序をもつ新規抗菌薬候補化合物を同定した。細菌内の核酸代謝経路を標的とし、in vitroで細胞毒性や既存の抗菌薬との交叉耐性を持たない核酸アナログだけでなく薬剤耐性遺伝子そのものを破壊しAMRを薬剤感受性菌に戻すという全く新しい作用を発揮する新規化合物の同定に成功した [ACS Infect Dis. 2019]。

  6. 休眠遺伝子の覚醒で産生される活性天然物をシーズとする難治性疾患治療薬の網羅的開発

    児玉 栄一, 大島 吉輝, 浅井 禎吾

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    研究種目:Grant-in-Aid for Scientific Research (B)

    研究機関:Tohoku University

    2016年4月1日 ~ 2019年3月31日

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    植物・微生物の休眠遺伝子を覚醒させ、新規天然物を効率よく創出した。さらにそれを中間体として化学修飾を加え、化学合成では創生できない複数の化合物ライブラリーを構築した。我々が確立した代表的なウイルスと種々のがん細胞に対する革新的スクリーニング法を駆使し、メロテルペノイド系ライブラリーに、破骨細胞における酵素活性抑制効果とウイルス関連悪性腫瘍に特異的に効果を示すことを見出し、NMR解析にて構造を決定した。耐性HIVにも効果を示す逆転写酵素阻害剤も見出すことができた。ケミカルバイオロジー手技を応用し、学理的創薬、難治性疾患治療の向上やunmet medical needsに資する成果を得た。

  7. 耐性機序を標的とした抗HIV剤の基礎的研究

    児玉 栄一

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    研究種目:Grant-in-Aid for Challenging Exploratory Research

    研究機関:Tohoku University

    2013年4月1日 ~ 2016年3月31日

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    本研究はexcisionによって耐性化した抗ウイルス剤の感受性を回復させる化合物を見出し、逆転写酵素における生化学・薬理学・構造生物学の3分野へ波及・拡大を目指す一方で、出口を臨床応用に定めるものである。本研究期間でアッセイ系の構築、5000超のスクリーニングから、ヒットを見出し、現在リード化合物の生成・取得を試みている。一方でこれらの知見からケミカルバイオロジーツールとしてレトロトランスポゾン活性の阻害効果についても検討し、細胞分化の調整に用いることができることを明らかとし、他分野への応用を実証した。

  8. 免疫淘汰圧に相乗効果を示す抗ウイルス剤の開発

    児玉 栄一, 上野 貴将

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    研究種目:Grant-in-Aid for Scientific Research (B)

    研究機関:Tohoku University

    2012年4月1日 ~ 2015年3月31日

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    HIVの宿主免疫を回避する機能を解明・阻害するために、免疫機能に重要なシグナル伝達を阻害するHIVアクセサリ-タンパクNefに注目し、免疫回避に重要な部位の新規同定、詳細な機能解析と免疫回避機能を阻害しうる創薬研究を行った。また免疫不全が進行しない患者におけるNef機能が、通常の患者のそれとは異なることを示した。これまで融合することがなかった免疫学と創薬科学、そして構造生物学知見を加えた融合研究領域の提案から臨床応用への橋渡しを目指す基礎研究成果を得た。

  9. デング熱、デング出血熱の新しいバイオマーカーの有用性

    服部 俊夫, 仁木 敏朗, 平島 光臣, C.-Y. HAORILE, 久保 亨, 児玉 栄一

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    研究種目:Grant-in-Aid for Scientific Research (A)

    研究機関:Tohoku University

    2011年4月1日 ~ 2015年3月31日

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    デングウイルス(DENV)感染者における新規バイオマーカーとしてのGalectin 9 (Gal-9)とOsteopontin (OPN)の臨床的な有用性を研究した。血漿Gal-9はDENV感染者では正常群と比べ有意に上昇し、ヒトでの報告された最高の値を示し、回復期では有意に減少した。Gal-9値はヘマトクリット値、血小板数、単球およびウイルスRNAのコピー数と相関していた。血漿OPNも9倍以上の増加を急性期で示し、回復期ではトロンビン切断型のOPNが上昇し、免疫と凝固のクロストークマーカーと思われた。故に、DENV感染における血漿Gal-9及びOPNが病態反映のマーカーである可能性を示した。

  10. Translocation defective逆転写酵素阻害剤に対する耐性機序

    芦野 有悟, 児玉 栄一

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    研究種目:Grant-in-Aid for Scientific Research (C)

    研究機関:Tohoku University

    2011年4月28日 ~ 2014年3月31日

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    核酸系逆転写酵素阻害剤4'-ethynyl-2-fluoro-deoxyadenosine (EFdA)はtranslocation活性を阻害する。作用機序解明のためEFdA耐性HIVを誘導し、耐性責任変異M184I/V、2次変異A158T、T165M/Rを同定した。M184I/Vは複製能を低下させたが、2次変異の一部は複製能を回復させた。逆転写酵素アッセイの結果はウイルスアッセイのそれに一致した。複数作製した多剤耐性HIVに対してEFdAは非常に強い活性を有していた。本研究ではtranslocation阻害に必要な逆転写酵素アミノ酸の同定、分子レベルでの薬剤のデザインのための基盤を形成した。

  11. 本邦で見出された新規多剤耐性変異N348IのHIV逆転写酵素に及ぼす影響に関する研究

    児玉 栄一

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    研究種目:Grant-in-Aid for Scientific Research (C)

    研究機関:Tohoku University

    2009年 ~ 2011年

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    HIV逆転写酵素(RT)の多剤耐性変異N348Iは取り込まれた核酸系RT阻害剤を除去し、他の変異と組み合わせでさらなる高度耐性をもたらす。非核酸系RT阻害剤に対しては、酵素への結合能低下が耐性機序であった。さらに新たな耐性変異K70QやA376Sを同定した。新規RT阻害剤がこれらのウイルスを阻害できることを見出した。本研究は、臨床サンプル解析、新規変異の獲得状況、耐性メカニズム解析、有用な薬剤の同定から、難治性HIV感染症のさらなる治療効果の増強に役立つと思われる。

  12. Revを標的とした新規抗HIV療法の確立

    児玉 栄一

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    研究種目:Grant-in-Aid for Scientific Research (C)

    研究機関:Kyoto University

    2005年 ~ 2006年

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    多剤併用療法によっても未だ完全なヒト免疫不全症ウイルス(HIV)の駆逐は不可能であり、既存の分子標的だけでなく、新しい分子標的に対する薬剤の開発が必要不可欠である。本研究ではウイルス複製に必須なアクセサリー蛋白のひとつであるRevを治療標的とする基盤研究を行ってきた。 レトロウイルスベクターによってRevペプチドを細胞内で発現させるとHIV複製を抑制できることから、種々の部位を含むRevペプチドをMT-2細胞で発現させ、その抗HIV部位を調べた。アルギニンリッチなヘリックス構造をとる部位が最も強い効果を示し、以前報告されたRev阻害蛋白であるRevM10と同レベルのHIV複製阻害能をもつことを明らかとした。また、同じレトロウイルス属のHTLV-IのRex蛋白のアルギニンリッチ部位でも同じような阻害効果を確認した。また、これらのペプチドは、17アミノ酸まで小分子化可能であることを明らかとした。これらのペプチドを化学合成し、感染細胞に加えたところ、HIVコレセプターであるCXCR4とHIV gp120の結合も阻害することを明らかとした。この方法では十分に細胞内にペプチドが導入されておらず、現在までに報告のある新たな方法で導入を試みているが現時点では有効な方法は見出されていない。このため、当研究期間内には新規治療法の確立には至っていないが、当研究期間中に得られた結果を踏まえて今後さらなるRevペプチドの作用機序解明を行う。さらにペプチドの縮小化、改変を行い、現在臨床治療上、最大の問題となっている薬剤耐性ウイルスの克服戦略を構築する。また、これらの研究成果からRNAウイルスにおけるゲノムの核外移行に関してだけでなく、宿主細胞におけるRNAの核外移行に関しても新しい知見を得ることを目標とする。

  13. ヘルペスウイルスを標的とした新規治療薬開発による難治性腫瘍克服

    松岡 雅雄, 児玉 栄一

    2003年 ~ 2004年

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    内在性thymidine kinase(TK)欠損細胞株であるヒト骨肉腫細胞株143BにEBV-TK,KSHV-TK、ヒトTK遺伝子を発現させ、この細胞株に様々な核酸化合物を添加しMTTアッセイで細胞傷害作用を確認することによりTKでリン酸化される化合物をスクリーニングした。核酸系化合物をスクリーニングすることによりEBV-TK,KSHV-TK特異的に阻害効果を有する化合物を同定した.EBV-TK発現細胞株に対するEC50は0.049μg/mlであり、KSHV-TK発現細胞株に対するEC50は0.64μg/mlであった。EBV感染細胞株RPMI8866を用いてDNAメチル化阻害剤である5-aza-deoxy-cytidine (5-azaCdR)、Histone deacethylase阻害剤であるTrichostatin A(TSA)、butylateで処理することによって化合物に対する感受性の亢進を認めた。またEBV初感染により引き起こされるChronic EBV infectionに対する治療効果を確認するために末梢血リンパ球にB958より分離したEBVを感染させる系に薬剤を加え、その抑制効果を解析した。本化合物を加えることによりMTTアッセイで細胞数の減少を認め、primary infectionに対しても有効である可能性が示唆された。

  14. ヒト免疫不全症ウイルス・細胞融合機構の解明と治療への応用

    児玉 栄一

    2003年 ~ 2004年

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    In vitroにおけるgp41由来ペプチドに対する耐性機序を明らかにするため、gp41C末端heptad repeat由来ペプチドC34耐性HIV-1株を作製し、その耐性機序を解析した。その耐性ウイルスのgp120では連続する5アミノ酸が欠失しており(ΔFNSTW)、またgp41では計7つのアミノ酸置換が認められた(A30V、D36G、Q39H、I37T、I37K、N126K、L2041)。このうちI37T、I37KおよびN126Kは耐性化に関与しており、その中でもI37Kが耐性責任変異であったが、I37Kのみでは十分なC34耐性を得られず、高度耐性を獲得するためにはアミノ酸変異の蓄積が必要であることが示された。一方、A30V、D36GおよびL2041は複製能の向上に、gp120に認められたΔFNSTWは耐性度の上昇と複製能の向上の両方に関与していた。本研究の結果から、耐性に直接寄与する変異がまず導入されるが、それらは同時に複製能を低下させてしまうため複製能を向上させる変異が出現し、それらが交互に追加されてゆくことが示された。また、耐性責任変異であるI37KはC34との結合力を弱めるが、N126Kは、I37Kを有する変異N-HRとの結合力を回復させることを明らかとした。A30とD36における塩基置換は、ウイルスゲノムRNAを細胞核外へ輸送するRevタンパクが結合するRev responsive element (RRE)領域中に存在し、I37の置換によって変化したRREの2次構造を補正していた。さらにgp41コード領域はRREのみならず、tatやrevの一部をコードしていることから、HIVは融合阻害剤に対する変異を容易に導入することはできないと推測された。これらの結果は、HIV-1の融合阻害がHIV-1の化学療法における有効な標的の一つであることを示唆している。

  15. 新規HIV複製ステップの同定及びその阻害剤開発への応用

    児玉 栄一

    2001年 ~ 2001年

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    研究代表者は、Human immunodeficiency virus (HIV)の薬剤耐性化を克服するために新規阻害ステップの同定および新規核酸系逆転写酵素阻害剤の関発を行った。今年度は野耐性ウイルスを含めたHIV-1のみならず、HIV-2にも効果を示す核酸誘導体、4'-ethynyl-2'-deoxynucleoside(4'-E-dN)を同定した。4'-E-dNは今までに報告のある主な薬剤耐性株(AZT、ddI、ddC、d4T、3-TC耐性株)に対しても強い抗ウイルス効果を維持しており、多剤併用療法(HAART)施行後問題となっている多剤耐性臨床分離HIVの複製も野生株同様に阻害した。特に4'-E-2'-deoxycytidine、4'-E-2'-deoxyadenosine(4'-E-dA)、4'-E-2'-deoxyribofuranosyl-2,6-diaminopurineが強い抗HIV効果を示した。これらの薬剤が核酸系逆転写酵素阻害剤として作用していることを明らかとした。この作用機序をさらに解明するために4'-E-dA耐性ウイルスの誘導を試みたところ、約80倍耐性を示すウイルスを分離することができた。4'-E-dA耐性ウイルスの逆転写酵素領域の塩基配列を解析したところ、逆転写酵素領域にI142V/T165R/M184Vといった新規変異を見出した。4'-E-dAとその誘導体および3-TCに対してのみ交叉耐性を示した。種々の組み合わせの分子クローンを用いて解析したところ、T165RとM184Vが主な耐性責任変異であった。単一変異では耐性は獲得されていなかった。これらアミノ酸変異部位は現在報告されている逆転写酵素立体構造においてすべてRT活性中心近傍に位置し、特にT165はM184と対をなしており、sterichindranceによって耐性化することを明らかとした。

  16. 薬剤耐性HIVに著効を示す新規核酸誘導体の開発

    児玉 栄一

    2000年 ~ 2001年

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    研究代表者は、Human immunodeficiency virus(HIV)の薬剤耐性化を克服するために耐性ウイルスを含めたHIV-1のみならず、HIV-2にも効果を示す核酸誘導体、4'-ethyny1-2'-deoxynucleoside(4'-E-dN)を同定した。4'-E-dNは今までに報告のある主な薬剤耐性株(AZT、ddI、ddC、d4T、3-TC耐性株)に対しても強い抗ウイルス効果を維持しており、多剤併用療法(HAART)施行後問題となっている多剤耐性臨床分離HIVの複製も野生株同様に阻害した。特に4'-E-2'-deoxycytidine、4,-E-2'-deoxyadenosine(4'-E-dA)、4'-E-2'-deoxyribofuranosyl-2,6-diaminopurineが強い抗HIV効果を示した。これらの薬剤が核酸系逆転写酵素阻害剤として作用していることを明らかとした。この作用機序をさらに解明するために4'-E-dA耐性ウイルスの誘導を試みたところ、約80倍耐性をホすウイルスを分離することができた4'-E-dA耐性ウイルスの逆転写酵素領域の塩基配列を解析したところ、逆転写酵素領域にI142V/T165R/M184Vといった新規変異を見出した。4'-E-dAとその誘導体および3-TCに対してのみ交叉耐性を示した。種々の組み合わせの分子クローンを用いて解析したところ、T165RとM184Vが主な耐性責任変異であった。単一変異では耐性は獲得されていなかうた。これらアミノ酸変異部位は現在報告されている逆転写酵素立体構造においてすべてRT活性中心近傍に位置し、特にT165はM184と対をなしており、steric hindranceによって耐性化することを明らかとした。

  17. 新規HIV複製ステップの同定及びその阻害剤開発への応用

    児玉 栄一

    2000年 ~ 2000年

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    研究代表者は今まで同定されていないHIV複製ステップを阻害する薬剤(Y-664)を発見、報告した。Y-664はAZTとの併用で相乗効果が認められ、治療上問題となる多剤耐性HIVに対しても野生株と同様な効果を示した。また、Y-664は宿主細胞への吸着、進入および逆転写反応を阻害しないが、宿主細胞内でのウイルスDNAの合成を濃度依存的に阻害した。作用機序解明のためY-664に対する耐性HIVをin vitroで誘導し、約4倍の耐性度を示すHIVを分離した。このHIVの複製能は野生株と比べ低下していた。その変異部位をplasmid cloneであるpNL4-3と組み替え、解析したところpolおよびvifをコードする部位が耐性に関与していることが判明し、現在その詳細な解析を行っている。さらに作用機序が未だ解明されていない薬剤を18種同定し、そのうち14種類が宿主細胞への吸着からprovirus組み込みまでに関与していることを明らかとした。この研究で確立した方法を用い、耐性株に対して効果を示す新規核酸誘導体の作用機序を解明したところ、逆転写酵素阻害剤であると同定でき、その結果を論文にまとめることが可能であった。

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その他 7

  1. 安全かつ効果的な抗HIV療法開発のための研究

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    安全かつ効果的な抗HIV療法開発のための研究

  2. 人獣共通感染症病因の生態と病原性の分子基盤

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    人獣共通感染症の制圧に向けた基礎研究

  3. 人獣共通感染症病因の生態と病原性の分子基盤

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    人獣共通感染症病因の生態と病原性の分子基盤

  4. 抗ウイルス剤開発

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    抗ウイルス剤開発

  5. 抗ウイルス剤

  6. 抗HIV剤の適正使用

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    抗HIV剤の適正使用

  7. HIV吸着・膜融合過程を標的とする多剤耐性克服型HIV化学療法剤の開発

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    HIV吸着・膜融合過程を標的とする多剤耐性克服型HIV化学療法剤の開発

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