Details of the Researcher

PHOTO

Hironori Hayashi
Section
International Research Institute of Disaster Science
Job title
Assistant Professor
Degree

Research History 4

  • 2020/10 - Present
    東北大学 災害科学国際研究所　災害感染症学分野　助教

  • 2018/10 - 2021/09
    Tohoku University　Faculty of Medicine

  • 2018/04 - 2018/09
    東北大学病院　検査部　助教

  • 2014/10 - 2018/03
    国立国際医療研究センター　難治性ウイルス感染症研究部　研究員

Education 3

  • Kumamoto University　Graduate School of Medical Sciences

    2010/04 - 2014/09

  • 京都大学大学院　エネルギー科学研究科

    2005/04 - 2010/03

  • Kyoto University　Faculty of Engineering　School of Industrial Chemistry

    2001/04 - 2005/03

Committee Memberships 2

  • 東北大学　遺伝子組換え実験安全主任者

    2025/04 - Present

  • エイズ学会　代議員

    2023/12 - 2025/12

Research Areas 4

  • Life sciences / Molecular biology /

  • Life sciences / Structural biochemistry /

  • Life sciences / Bacteriology /

  • Life sciences / Virology /

Awards 5

  1. 日本エイズ学会ECC山口メモリアルエイズ研究奨励賞

    2016

  2. 第26回 抗ウイルス療法学会学術集会 塩田賞

    2016

  3. 熊本大学学長賞

    2014/09

  4. 日本学術振興会特別研究員

    2009/04

  5. 日本化学会第88回春季年会 学生講演賞

    2008/03

Papers 52

  1. Liquid-liquid phase separation and its regulation of the BACH2 intrinsically disordered region Peer-reviewed

    Hironori Hayashi, Miyuki Kato-Murayama, Takeshi Kurasawa, Eiichi N. Kodama, Mikako Shirouzu, Kazuhiko Igarashi, Kazutaka Murayama

    Biophysics and Physicobiology　e230010　2026/02/25

    Publisher: Biophysical Society of Japan

    DOI： 10.2142/biophysico.bppb-v23.0010 　

    eISSN： 2189-4779

  2. Impact of Single Halogen Atom Substitutions on Antiviral Profile of Inhibitors Targeting SARS-CoV-2 Main Protease

    Haydar Bulut, Nobuyo Higashi-Kuwata, Hiromi Ogata-Aoki, Hironori Hayashi, Nobutoki Takamune, Naoki Kishimoto, Debananda Das, Mi Li, Alexander Wlodawer, Shogo Misumi, Hirokazu Tamamura, Hiroaki Mitsuya

    ACS Omega　11　(3)　4541-4550　2026/01/14

    Publisher: American Chemical Society (ACS)

    DOI： 10.1021/acsomega.5c10895 　

    ISSN： 2470-1343

    eISSN： 2470-1343

  3. Genome Mining-Based Discovery of Pyrano[2,3-c]pyrrole Type Natural Products Possessing Alkyl Side Chain with Branched Methyl Groups. International-journal Peer-reviewed

    Yue Shi, Taro Ozaki, Yohei Morishita, Tohru Taniguchi, Hiroyasu Sato, Yoshitaka Aoyama, Akihiro Sugawara, Kaho Numata, Tomoya Fuse, Ryo Matsuda, Kento Hosotani, Hanako Fukano, Yoshihiko Hoshino, Aki Hirabayashi, Masato Suzuki, Jiro Yasuda, Rokusuke Yoshikawa, Hironori Hayashi, Eiichi N Kodama, Yoshitaka Shimotai, Hiroshi Hamamoto, Rohan A Davis, Teigo Asai

    Organic letters　27　(31)　8580-8585　2025/08/08

    DOI： 10.1021/acs.orglett.5c02504 　

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    Genome mining of polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) in fungal endophyte Neopestalotiopsis olumideae strain BRIP 39872 identified seven new natural products (olumilides A-D, D1, D1', D2) with pyrano[2,3-c]pyrrole scaffolds and their biosynthetic precursor preolumilide. Unlike known congeners, such as curvupallides, olumilides possess alkyl side chains with branched methyl groups and threonine-derived core scaffolds. Absolute configurations were determined by microED and ECD simulations, providing valuable information for further research focusing on the stereochemistry of PKS-NRPS reactions.

  4. Elucidation of Postfusion Structures of the Measles Virus F Protein for the Structure-Based Design of Fusion Inhibitors. International-journal Peer-reviewed

    Aoi Takahara, Toru Nakatsu, Kazushige Hirata, Hironori Hayashi, Kumi Kawaji, Keisuke Aoki, Shinsuke Inuki, Hiroaki Ohno, Hiroaki Kato, Eiichi Kodama, Shinya Oishi

    Journal of medicinal chemistry　68　(3)　3123-3133　2025/01/31

    DOI： 10.1021/acs.jmedchem.4c02337 　

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    Measles is a highly infectious disease and remains a major cause of childhood mortality worldwide. In some cases, the measles virus (MV) induces subacute sclerosing panencephalitis within several years of the acute infection. The infection of the target cells by MV is mediated by the F protein, in which two heptad repeat regions, HR1 and HR2, form a six-helix bundle before membrane fusion. We previously reported anti-MV peptides, which were designed from the HR region of the MV F protein. Here, we characterized the essential interactions between the HR1 and HR2 regions on the postfusion six-helix bundles of synthetic HR1 and HR2 peptides by crystallographic studies. Based on the crystal structures, we identified the minimal α-helix sequence for antiviral activity. Additionally, optimizing HR2 peptides by introducing α-helix-inducible motifs and maintaining key hydrogen bond networks at the N- and C-terminal regions led to the identification of highly potent antiviral peptides.

  5. An orally available P1'-5-fluorinated Mpro inhibitor blocks SARS-CoV-2 replication without booster and exhibits high genetic barrier. International-journal Peer-reviewed

    Nobuyo Higashi-Kuwata, Haydar Bulut, Hironori Hayashi, Kohei Tsuji, Hiromi Ogata-Aoki, Maki Kiso, Nobutoki Takamune, Naoki Kishimoto, Shin-Ichiro Hattori, Takahiro Ishii, Takuya Kobayakawa, Kenta Nakano, Yukiko Shimizu, Debananda Das, Junji Saruwatari, Kazuya Hasegawa, Kazutaka Murayama, Yoshikazu Sukenaga, Yuki Takamatsu, Kazuhisa Yoshimura, Manabu Aoki, Yuri Furusawa, Tadashi Okamura, Seiya Yamayoshi, Yoshihiro Kawaoka, Shogo Misumi, Hirokazu Tamamura, Hiroaki Mitsuya

    PNAS nexus　4　(1)　pgae578　2025/01

    DOI： 10.1093/pnasnexus/pgae578 　

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    We identified a 5-fluoro-benzothiazole-containing small molecule, TKB272, through fluorine-scanning of the benzothiazole moiety, which more potently inhibits the enzymatic activity of SARS-CoV-2's main protease (Mpro) and more effectively blocks the infectivity and replication of all SARS-CoV-2 strains examined including Omicron variants such as SARS-CoV-2XBB1.5 and SARS-CoV-2EG.5.1 than two Mpro inhibitors: nirmatrelvir and ensitrelvir. Notably, the administration of ritonavir-boosted nirmatrelvir and ensitrelvir causes drug-drug interactions warranting cautions due to their CYP3A4 inhibition, thereby limiting their clinical utility. When orally administered, TKB272 blocked SARS-CoV-2XBB1.5 replication without ritonavir in B6.Cg-Tg(K18-hACE2)2-Prlmn/J-transgenic mice, comparably as did ritonavir-boosted nirmatrelvir. When the ancestral SARS-CoV-2 was propagated with nirmatrelvir in vitro, a highly nirmatrelvir-resistant E166V-carrying variant (SARS-CoV-2E166V-P14) readily emerged by passage 14; however, when propagated with TKB272, no variants emerged by passage 25. SARS-CoV-2E166V showed some cross-resistance to TKB272 but was substantially sensitive to the compound. X-ray structural analyses and mass-spectrometric data showed that the E166V substitution disrupts the critical dimerization-initiating Ser1'-E166 interactions, thereby limiting nirmatrelvir's Mpro inhibition but that TKB272 nevertheless forms a tight binding with Mpro's catalytic active sight even in the presence of the E166V substitution. TKB272 shows no apparent genotoxicity as tested in the micro-Ames test. Highly potent TKB272 may serve as a COVID-19 therapeutic, overcome resistance to existing Mpro inhibitors.

  6. Binding of a potential antibacterial drug, mangiferin, to serine hydroxymethyltransferase from Enterococcus faecium. International-journal Peer-reviewed

    Hironori Hayashi, Kazuya Hasegawa, Erika Saijo, Eiich N Kodama, Kazutaka Murayama

    Biochemical and biophysical research communications　743　151177-151177　2024/12/12

    DOI： 10.1016/j.bbrc.2024.151177 　

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    Serine hydroxymethyltransferase (SHMT) plays a critical role in the 1C metabolism pathway. This pathway is involved in the synthesis of many amino and nucleic acids, and SHMT is considered a target for drugs through folate metabolism, especially for cancer and malaria. A detailed analysis of the interactions between SHMTs and drugs will greatly contribute to the development of new drugs. An anthraquinone compound was found in a compound library screening against SHMT from Enterococcus faecium (efmSHMT), from which mangiferin was implied as a compound that binds to efmSHMT. The binding assay indicated that mangiferin could bind to efmSHMT, and crystal structure analysis revealed interactions between efmSHMT and mangiferin at the binding site. Mangiferin bound to the binding site, turning the glucose moiety inward, which was supported by the docking model study. Although mangiferin does not share its molecular structure with other known inhibitors, such as pyrazolopyran-based compounds, the complex structure of the binding site did not differ much from those of other structures. The ligand binding site of efmSHMT may possess a preferred conformation.

  7. SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase. International-journal Peer-reviewed

    Hironori Hayashi, Erika Saijo, Kazushige Hirata, Shumei Murakami, Haruka Okuda, Eiichi N Kodama, Kazuya Hasegawa, Kazutaka Murayama

    Archives of biochemistry and biophysics　761　110160-110160　2024/09/21

    DOI： 10.1016/j.abb.2024.110160 　

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    Novel classes of antibiotics are needed to improve the resilience of the healthcare system to antimicrobial resistance (AMR), including vancomycin resistance. vanA gene cluster is a cause of vancomycin resistance. This gene cluster is transferred and spreads vancomycin resistance from Enterococcus spp. to Staphylococcus aureus. Therefore, novel antibacterial agents are required to combat AMR, including vanA-type vancomycin resistance. Serine hydroxymethyltransferase (SHMT) is a key target of antibacterial agents. However, the specific binding mechanisms of SHMT inhibitors remain unclear. Detailed structural information will contribute to understanding these mechanisms. In this study, we found that (+)-SHIN-2, the first in vivo active inhibitor of human SHMT, is strongly bound to the Enterococcus faecium SHMT (efmSHMT). Comparison of the crystal structures of apo- and (+)-SHIN-2-boud efmSHMT revealed that (+)-SHIN-2 stabilized the active site loop of efmSHMT via hydrogen bonds, which are critical for efmSHMT inhibition. Additionally, (+)-SHIN-2 formed hydrogen bonds with serine, forming the Schiff's base with pyridoxal 5'-phosphate, which is a co-factor of SHMT. Furthermore, (+)-SHIN-2 exerted biostatic effects on vancomycin-susceptible and vanA-type vancomycin-resistant E. faecium in vitro, indicating that SHMT inhibitors do not induce cross-resistance to vanA-type vancomycin. Overall, these findings can aid in the design of novel SHMT inhibitors to combat AMR, including vancomycin resistance.

  8. Structural and virologic mechanism of the emergence of resistance to Mpro inhibitors in SARS-CoV-2. International-journal Peer-reviewed

    Shin-Ichiro Hattori, Haydar Bulut, Hironori Hayashi, Naoki Kishimoto, Nobutoki Takamune, Kazuya Hasegawa, Yuri Furusawa, Seiya Yamayoshi, Kazutaka Murayama, Hirokazu Tamamura, Mi Li, Alexander Wlodawer, Yoshihiro Kawaoka, Shogo Misumi, Hiroaki Mitsuya

    Proceedings of the National Academy of Sciences of the United States of America　121　(37)　e2404175121　2024/09/10

    DOI： 10.1073/pnas.2404175121 　

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    We generated SARS-CoV-2 variants resistant to three SARS-CoV-2 main protease (Mpro) inhibitors (nirmatrelvir, TKB245, and 5h), by propagating the ancestral SARS-CoV-2WK521WT in VeroE6TMPRSS2 cells with increasing concentrations of each inhibitor and examined their structural and virologic profiles. A predominant E166V-carrying variant (SARS-CoV-2WK521E166V), which emerged when passaged with nirmatrelvir and TKB245, proved to be resistant to the two inhibitors. A recombinant SARS-CoV-2E166V was resistant to nirmatrelvir and TKB245, but sensitive to 5h. X-ray structural study showed that the dimerization of Mpro was severely hindered by E166V substitution due to the disruption of the presumed dimerization-initiating Ser1'-Glu166 interactions. TKB245 stayed bound to MproE166V, whereas nirmatrelvir failed. Native mass spectrometry confirmed that nirmatrelvir and TKB245 promoted the dimerization of Mpro, and compromised the enzymatic activity; the Ki values of recombinant MproE166V for nirmatrelvir and TKB245 were 117±3 and 17.1±1.9 µM, respectively, indicating that TKB245 has a greater (by a factor of 6.8) binding affinity to MproE166V than nirmatrelvir. SARS-CoV-2WK521WT selected with 5h acquired A191T substitution in Mpro (SARS-CoV-2WK521A191T) and better replicated in the presence of 5h, than SARS-CoV-2WK521WT. However, no significant enzymatic or structural changes in MproA191T were observed. The replicability of SARS-CoV-2WK521E166V proved to be compromised compared to SARS-CoV-2WK521WT but predominated over SARS-CoV-2WK521WT in the presence of nirmatrelvir. The replicability of SARS-CoV-2WK521A191T surpassed that of SARS-CoV-2WK521WT in the absence of 5h, confirming that A191T confers enhanced viral fitness. The present data should shed light on the understanding of the mechanism of SARS-CoV-2's drug resistance acquisition and the development of resistance-repellant COVID-19 therapeutics.

  9. Janus-Type Immunofluorescent Probes and a Quantitative Immunoassay System. International-journal Peer-reviewed

    Hiroshi Yabu, Misako Suzuki, Kazushige Matsukawa, Ikuma Maeda, Sigeo Ihara, Koshiro Yaegashi, Kentaro Totsu, Hironori Hayashi, Eiichi Kodama

    Langmuir : the ACS journal of surfaces and colloids　2024/08/15

    DOI： 10.1021/acs.langmuir.4c01911 　

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    To realize highly sensitive immunoassays, high optical density probes conjugated with antibodies for target antigens have been demanded in order to increase the visibility of antigen-antibody complex formation. We herein demonstrate the development of an immunoassay system using magnetic and fluorescent Janus particles as probes in conjunction with an antibody-immobilized microfluidic device. The concentration of the detection limit at which there was a significant difference between SARS-CoV-2 and human coronavirus 229E antigens was 3.1 ng/mL, and the standard deviation of the signal was less than 5%. The immunofluorescent probe and immunoassay system developed in this study are expected to be applicable not only to SARS-CoV-2 but also to the quantitative measurement of various other disease marker proteins and biomolecules.

  10. Synthesis and Cytotoxicity of Cyclic Octapeptide Surugamides with Varied N-Acyl Moieties. Peer-reviewed

    Kenichi Matsuda, Shinya Niikura, Rintaro Ichihara, Kei Fujita, Anna M Strasser, Rokusuke Yoshikawa, Jiro Yasuda, Yoshiki Hiramatsu, Hironori Hayashi, Eiichi N Kodama, Toshiyuki Wakimoto

    Chemical & pharmaceutical bulletin　72　(9)　826-830　2024/08

    DOI： 10.1248/cpb.c24-00533 　

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    Surugamides are a group of non-ribosomal peptides produced by Streptomyces spp. Several derivatives possess acyl groups, which are proposed to be attached to a lysine side chain after backbone-macrocyclization during biosynthesis. To date, five different acyl groups have been identified in nature, yet their impacts on biological activity remain underexplored. Here we synthesized surugamide B derivatives with varied acyl moieties. Biological evaluations revealed that larger hydrophobic acyl groups on lysine ε-NH2 enhance cytotoxicity.

  11. Helical peptides with disordered regions for measles viruses provide new generalized insights into fusion inhibitors. International-journal Peer-reviewed

    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　2024/02/16

    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.

  12. GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants. International-journal Peer-reviewed

    Manabu Aoki, Hiromi Aoki-Ogata, Haydar Bulut, Hironori Hayashi, Nobutoki Takamune, Naoki Kishimoto, Hiroki Tanaka, Nobuyo Higashi-Kuwata, Shin-Ichiro Hattori, Debananda Das, Kalapala Venkateswara Rao, Kazuya Iwama, David A Davis, Kazuya Hasegawa, Kazutaka Murayama, Robert Yarchoan, Arun K Ghosh, Alice K Pau, Shinichi Machida, Shogo Misumi, Hiroaki Mitsuya

    Science advances　9　(28)　eadg2955　2023/07/14

    DOI： 10.1126/sciadv.adg2955 　

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    Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIVKGD) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIVKGD was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC50 of 130 femtomolar. When cells were exposed to HIVKGD IN-containing recombinant HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142. X-ray crystallographic analyses revealed that GRL-142 interacts with NLS's putative sequence (DQAEHLK) and sterically blocks the nuclear transport of GRL-142-bound HIVKGD's PIC. Highly INSTI-resistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to GRL-142, suggesting that NLS-targeting agents would serve as salvage therapy agents for highly INSTI-resistant variant-harboring individuals. The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.

  13. Establishing an accurate and sensitive in vitro drug screening system for human adenovirus infection with human corneal cells Peer-reviewed

    Mina Sasano, Hironori Hayashi, Kumi Kawaji, Emiko Usui, Eiich N. Kodama

    Virology　581　34-38　2023/04

    Publisher: Elsevier BV

    DOI： 10.1016/j.virol.2023.02.005 　

    ISSN： 0042-6822

  14. Identification of SARS-CoV-2 Mpro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2. International-journal Peer-reviewed

    Higashi-Kuwata N, Tsuji K, Hayashi H, Bulut H, Kiso M, Imai M, Ogata-Aoki H, Ishii T, Kobayakawa T, Nakano K, Takamune N, Kishimoto N, Hattori SI, Mitsuya H

    Nature communications　14　(1)　1076-1076　2023/02/25

    DOI： 10.1038/s41467-023-36729-0 　

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    COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro's active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.

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

    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

    Publisher: 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.

  16. Potent and biostable inhibitors of the main protease of SARS-CoV-2. International-journal Peer-reviewed

    Kohei Tsuji, Takahiro Ishii, Takuya Kobayakawa, Nobuyo Higashi-Kuwata, Chika Azuma, Miyuki Nakayama, Takato Onishi, Hiroki Nakano, Naoya Wada, Miki Hori, Kouki Shinohara, Yutaro Miura, Takuma Kawada, Hironori Hayashi, Shin-Ichiro Hattori, Haydar Bulut, Debananda Das, Nobutoki Takamune, Naoki Kishimoto, Junji Saruwatari, Tadashi Okamura, Kenta Nakano, Shogo Misumi, Hiroaki Mitsuya, Hirokazu Tamamura

    iScience　25　(11)　105365-105365　2022/11/18

    DOI： 10.1016/j.isci.2022.105365 　

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    Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection in vitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

  17. Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors. International-journal Peer-reviewed

    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　2022/06/23

    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.

  18. Disseminated tuberculosis with paradoxical reactions caused by a Mycobacterium tuberculosis strain belonging to the Indo-Oceanic lineage: An imported case in Japan. International-journal Peer-reviewed

    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　2022/03/04

    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.

  19. Fluorine Modifications Contribute to Potent Antiviral Activity against Highly Drug-Resistant HIV-1 and Favorable Blood-Brain Barrier Penetration Property of Novel Central Nervous System-Targeting HIV-1 Protease Inhibitors In Vitro. International-journal Peer-reviewed

    Masayuki Amano, Ravikiran S Yedidi, Pedro Miguel Salcedo-Gómez, Hironori Hayashi, Kazuya Hasegawa, Cuthbert D Martyr, Arun K Ghosh, Hiroaki Mitsuya

    Antimicrobial agents and chemotherapy　66　(2)　e0171521　2022/02/15

    DOI： 10.1128/AAC.01715-21 　

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    To date, there are no specific treatment regimens for HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). Here, we report that two newly generated CNS-targeting HIV-1 protease (PR) inhibitors (PIs), GRL-08513 and GRL-08613, which have a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring and P2-tetrahydropyrano-tetrahydrofuran (Tp-THF) with a sulfonamide isostere, are potent against wild-type HIV-1 strains and multiple clinically isolated HIV-1 strains (50% effective concentration [EC50]: 0.0001 to ∼0.0032 μM). As assessed with HIV-1 variants that had been selected in vitro to propagate at a 5 μM concentration of each HIV-1 PI (atazanavir, lopinavir, or amprenavir), GRL-08513 and GRL-08613 efficiently inhibited the replication of these highly PI-resistant variants (EC50: 0.003 to ∼0.006 μM). GRL-08513 and GRL-08613 also maintained their antiviral activities against HIV-2ROD as well as severely multidrug-resistant clinical HIV-1 variants. Additionally, when we assessed with the in vitro blood-brain barrier (BBB) reconstruction system, GRL-08513 and GRL-08613 showed the most promising properties of CNS penetration among the evaluated compounds, including the majority of FDA-approved combination antiretroviral therapy (cART) drugs. In the crystallographic analysis of compound-PR complexes, it was demonstrated that the Tp-THF rings at the P2 moiety of GRL-08513 and GRL-08613 form robust hydrogen bond interactions with the active site of HIV-1 PR. Furthermore, both the P1-3,5-bis-fluorophenyl- and P1-para-monofluorophenyl rings sustain greater contact surfaces and form stronger van der Waals interactions with PR than is the case with darunavir-PR complex. Taken together, these results strongly suggest that GRL-08513 and GRL-08613 have favorable features for patients infected with wild-type/multidrug-resistant HIV-1 strains and might serve as candidates for a preventive and/or therapeutic agent for HAND and other CNS complications.

  20. Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic Site Integrase Inhibitor, JTP-0157602. International-journal Peer-reviewed

    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)　JVI0184321　2022/01/19

    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.

  21. A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication. International-journal Peer-reviewed

    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　2021/01/28

    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.

  22. Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity. International-journal Peer-reviewed

    Haydar Bulut, Shin-Ichiro Hattori, Hiromi Aoki-Ogata, Hironori Hayashi, Debananda Das, Manabu Aoki, David A Davis, Kalapala Venkateswara Rao, Prasanth R Nyalapatla, Arun K Ghosh, Hiroaki Mitsuya

    Scientific reports　10　(1)　10664-10664　2020/06/30

    DOI： 10.1038/s41598-020-65993-z 　

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    HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2'-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PRWT) and highly-multi-PI-resistance-associated PRDRVRP51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2'-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier.

  23. Pyrimidine Analogues as a New Class of Gram-Positive Antibiotics, Mainly Targeting Thymineless-Death Related Proteins. International-journal Peer-reviewed

    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　2020/06/12

    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.

  24. Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones. International-journal Peer-reviewed

    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　2020/04/14

    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.

  25. Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5. International-journal Peer-reviewed

    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

    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.

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

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

    Antiviral Chemistry and Chemotherapy　28　204020662092131-204020662092131　2020/01

    Publisher: 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.

  27. Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib-sensitive and -resistant multiple myeloma cells. International-journal Peer-reviewed

    Nao Nishimura, Mohamed O Radwan, Masayuki Amano, Shinya Endo, Eri Fujii, Hironori Hayashi, Shikiko Ueno, Niina Ueno, Hiro Tatetsu, Hiroyuki Hata, Yoshinari Okamoto, Masami Otsuka, Hiroaki Mitsuya, Masao Matsuoka, Yutaka Okuno

    Cancer science　110　(10)　3275-3287　2019/10

    DOI： 10.1111/cas.14154 　

    ISSN： 1347-9032

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    p97/VCP is an endoplasmic reticulum (ER)-associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER-associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell-based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC50 , 100-500 nmol/L). OSSL_325096 induced apoptosis in myeloma cell lines, including a bortezomib-resistant cell line and primary myeloma cells purified from patients. Accumulation of poly-ubiquitinated proteins, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly-ubiquitinated protein. IC50 of OSSL_325096 to myeloma cell lines were found to be lower (0.1-0.8 μmol/L) than those of DBeQ (2-5 μmol/L). In silico protein-drug-binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell-free ATPase assays, OSSL_325096 showed dose-dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti-myeloma activity, at least in part through p97/VCP inhibition.

  28. Novel Protease Inhibitors Containing C-5-Modified bis-Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2' Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug Resistance. International-journal Peer-reviewed

    Yuki Takamatsu, Manabu Aoki, Haydar Bulut, Debananda Das, Masayuki Amano, Venkata Reddy Sheri, Ladislau C Kovari, Hironori Hayashi, Nicole S Delino, Arun K Ghosh, Hiroaki Mitsuya

    Antimicrobial agents and chemotherapy　63　(8)　2019/08

    DOI： 10.1128/AAC.00372-19 　

    ISSN： 0066-4804

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    Combination antiretroviral therapy has achieved dramatic reductions in the mortality and morbidity in people with HIV-1 infection. Darunavir (DRV) represents a most efficacious and well-tolerated protease inhibitor (PI) with a high genetic barrier to the emergence of drug-resistant HIV-1. However, highly DRV-resistant variants have been reported in patients receiving long-term DRV-containing regimens. Here, we report three novel HIV-1 PIs (GRL-057-14, GRL-058-14, and GRL-059-14), all of which contain a P2-amino-substituted-bis-tetrahydrofuranylurethane (bis-THF) and a P2'-cyclopropyl-amino-benzothiazole (Cp-Abt). These PIs not only potently inhibit the replication of wild-type HIV-1 (50% effective concentration [EC50], 0.22 nM to 10.4 nM) but also inhibit multi-PI-resistant HIV-1 variants, including highly DRV-resistant HIVDRVRP51 (EC50, 1.6 nM to 30.7 nM). The emergence of HIV-1 variants resistant to the three compounds was much delayed in selection experiments compared to resistance to DRV, using a mixture of 11 highly multi-PI-resistant HIV-1 isolates as a starting HIV-1 population. GRL-057-14 showed the most potent anti-HIV-1 activity and greatest thermal stability with wild-type protease, and potently inhibited HIV-1 protease's proteolytic activity (Ki value, 0.10 nM) among the three PIs. Structural models indicate that the C-5-isopropylamino-bis-THF moiety of GRL-057-14 forms additional polar interactions with the active site of HIV-1 protease. Moreover, GRL-057-14's P1-bis-fluoro-methylbenzene forms strong hydrogen bonding and effective van der Waals interactions. The present data suggest that the combination of C-5-aminoalkyl-bis-THF, P1-bis-fluoro-methylbenzene, and P2'-Cp-Abt confers highly potent activity against wild-type and multi-PI-resistant HIV strains and warrant further development of the three PIs, in particular, that of GRL-057-14, as potential therapeutic for HIV-1 infection and AIDS.

  29. Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications. International-journal Peer-reviewed

    Amano M, Salcedo-Gómez PM, Yedidi RS, Zhao R, Hayashi H, Hasegawa K, Nakamura T, Martyr CD, Ghosh AK, Mitsuya H

    Antimicrobial agents and chemotherapy　63　(7)　2019/05

    DOI： 10.1128/AAC.00466-19 　

    ISSN： 0066-4804

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    There is currently no specific therapeutics for the HIV-1-related central nervous system (CNS) complications. Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring, and P2-bis-tetrahydrofuran (bis-THF) or P2-tetrahydropyrano-tetrahydrofuran (Tp-THF), with a sulfonamide isostere, are highly active against wild-type HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0002 to ∼0.003 μM), with minimal cytotoxicity. These CNS-targeting PIs efficiently suppressed the replication of HIV-1 variants (EC50, 0.002 to ∼0.047 μM) that had been selected to propagate at high concentrations of conventional HIV-1 PIs. Such CNS-targeting PIs maintained their antiviral activity against HIV-2ROD as well as multidrug-resistant clinical HIV-1 variants isolated from AIDS patients who no longer responded to existing antiviral regimens after long-term therapy. Long-term drug selection experiments revealed that the emergence of resistant-HIV-1 against these CNS-targeting PIs was substantially delayed. In addition, the CNS-targeting PIs showed the most favorable CNS penetration properties among the tested compounds, including various FDA-approved anti-HIV-1 drugs, as assessed with the in vitro blood-brain barrier reconstruction system. Crystallographic analysis demonstrated that the bicyclic rings at the P2 moiety of the CNS-targeting PIs form strong hydrogen-bond interactions with HIV-1 protease (PR) active site. Moreover, both the P1-3,5-bis-fluorophenyl and P1-para-monofluorophenyl rings sustain greater van der Waals contacts with PR than in the case of darunavir (DRV). The data suggest that the present CNS-targeting PIs have desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 strains and might serve as promising preventive and/or therapeutic candidates for HIV-1-associated neurocognitive disorders (HAND) and other CNS complications.

  30. Halogen bond interactions of novel HIV-1 protease inhibitors (PI)(GRL-001-15 and GRL-003-15) with the flap of protease are critical for their potent activity against wild-type and multi-PI-resistant HIV-1 variants. International-journal Peer-reviewed

    Hattori SI, Hayashi H, Bulut H, Rao KV, Nyalapatla PR, Hasegawa K, Aoki M, Ghosh AK, Mitsuya H

    Antimicrobial agents and chemotherapy　63　(6)　2019/04

    DOI： 10.1128/AAC.02635-18 　

    ISSN： 0066-4804

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    We generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2'-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2' ligands, respectively. GRL-001-15 and GRL-003-15 have meta-monofluorophenyl and para-monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50% effective concentrations (EC50s) of 57 and 50 pM, respectively, and have favorable cytotoxicity profiles with 50% cytotoxic concentrations (CC50s) of 38 and 11 μM, respectively. The activity of GRL-001-15 against multi-PI-resistant HIV-1 variants was generally greater than that of GRL-003-15. The EC50 of GRL-001-15 against an HIV-1 variant that was highly resistant to multiple PIs, including darunavir (DRV) (HIV-1DRV R P30), was 0.17 nM, and that of GRL-003-15 was 3.3 nM, while DRV was much less active, with an EC50 of 216 nM. The emergence of HIV-1 variants resistant to GRL-001-15 and GRL-003-15 was significantly delayed compared to that of variants resistant to selected PIs, including DRV. Structural analyses of wild-type protease (PRWT) complexed with the novel PIs revealed that GRL-001-15's meta-fluorine atom forms halogen bond interactions (2.9 and 3.0 Å) with Gly49 and Ile50, respectively, of the protease flap region and with Pro81' (2.7 and 3.2 Å), which is located close to the protease active site, and that two fluorine atoms of GRL-142-13 form multiple halogen bond interactions with Gly49, Ile50, Pro81', Ile82', and Arg8'. In contrast, GRL-003-15 forms halogen bond interactions with Pro81' alone, suggesting that the reduced antiviral activity of GRL-003-15 is due to the loss of the interactions with the flap region.

  31. Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies. Peer-reviewed

    Ghosh AK, Williams JN, Ho RY, Simpson HM, Hattori SI, Hayashi H, Agniswamy J, Wang YF, Weber IT, Mitsuya H

    Journal of medicinal chemistry　61　(21)　9722-9737　2018/11

    DOI： 10.1021/acs.jmedchem.8b01227 　

    ISSN： 0022-2623

  32. The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase. International-journal Peer-reviewed

    Yuki Takamatsu, Debananda Das, Satoru Kohgo, Hironori Hayashi, Nicole S Delino, Stefan G Sarafianos, Hiroaki Mitsuya, Kenji Maeda

    Cell chemical biology　25　(10)　1268-1278　2018/10/18

    DOI： 10.1016/j.chembiol.2018.07.014 　

    ISSN： 2451-9456

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    4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA/MK-8591), a nucleoside reverse transcriptase inhibitor (NRTI) under clinical trials, is a potent and promising long-acting anti-HIV type 1 (HIV-1) agent. EFdA and its derivatives possess a modified 4'-moiety and potently inhibit the replication of a wide spectrum of HIV-1 strains resistant to existing NRTIs. Here, we report that EFdA and NRTIs with a 4'-ethynyl- or 4'-cyano-moiety exerted activity against HIV-1 with an M184V mutation and multiple NRTI-resistant HIV-1s, whereas NRTIs with other moieties (e.g., 4'-methyl) did not show this activity. Structural analysis indicated that EFdA and 4'-ethynyl-NRTIs (but not other 4'-modified NRTIs), formed strong van der Waals interactions with critical amino acid residues of reverse transcriptase. Such interactions were maintained even in the presence of a broad resistance-endowing M184V substitution, thus potently inhibiting drug-resistant HIV-1 strains. These findings also explain the mechanism for the potency of EFdA and provide insights for further design of anti-HIV-1 therapeutics.

  33. GRL-079, a novel HIV-1 protease inhibitor, is extremely potent against multidrug-resistant HIV-1 variants and has a high genetic barrier against the emergence of resistant variants Peer-reviewed

    Nicole S. Delino, Manabu Aoki, Hironori Hayashi, Shin-ichiro Hattori, Simon B. Chang, Yuki Takamatsu, Cuthbert D. Martyr, Debananda Das, Arun K. Ghosh, Hiroaki Mitsuya

    Antimicrobial Agents and Chemotherapy　62　(5)　2018/05/01

    Publisher: American Society for Microbiology

    DOI： 10.1128/AAC.02060-17 　

    ISSN： 1098-6596 0066-4804

  34. Mechanism of Darunavir (DRV)‘s high genetic barrier to HIV-1 resistance: A key V32I substitution in protease rarely occurs, but once it occurs, it predisposes HIV-1 To develop DRV resistance Peer-reviewed

    Manabu Aoki, Debananda Das, Hironori Hayashi, Hiromi Aoki-Ogata, Yuki Takamatsu, Arun K. Ghosh, Hiroaki Mitsuya

    mBio　9　(2)　2018/03/01

    Publisher: American Society for Microbiology

    DOI： 10.1128/mBio.02425-17 　

    ISSN： 2150-7511 2161-2129

  35. HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir. International-journal Peer-reviewed

    Yoshiaki Yasutake, Shin-Ichiro Hattori, Hironori Hayashi, Kouki Matsuda, Noriko Tamura, Satoru Kohgo, Kenji Maeda, Hiroaki Mitsuya

    Scientific reports　8　(1)　1624-1624　2018/01/26

    DOI： 10.1038/s41598-018-19602-9 　

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    Hepatitis B virus (HBV) reverse transcriptase (RT) is essential for viral replication and is an important drug target. Nonetheless, the notorious insolubility of HBV RT has hindered experimental structural studies and structure-based drug design. Here, we demonstrate that a Q151M substitution alone at the nucleotide-binding site (N-site) of human immunodeficiency virus type-1 (HIV-1) RT renders HIV-1 highly sensitive to entecavir (ETV), a potent nucleoside analogue RT inhibitor (NRTI) against HBV. The results suggest that Met151 forms a transient hydrophobic interaction with the cyclopentyl methylene of ETV, a characteristic hydrophobic moiety of ETV. We thus solved the crystal structures of HIV-1 RTQ151M:DNA complex with bound dGTP or ETV-triphosphate (ETV-TP). The structures revealed that ETV-TP is accommodated at the N-site slightly apart from the ribose ring of the 3'-end nucleotide, compared to the position of bound dGTP and previously reported NRTI/dNTP. In addition, the protruding methylene group of bound ETV-TP directly pushes the side-chain of Met184 backward. Met184 is a key residue that confers ETV resistance upon substitution with smaller Ile/Val. These results provide novel insights into NRTI binding to the N-site and further provide important clues for the development of novel anti-HBV/HIV-1 RT inhibitors to overcome critical drug resistance.

  36. Structural basis of unprecedented potency of GRL-142 against multi-drug resistant HIV-1 protease Peer-reviewed

    Das Debananda, Aoki Manabu, Hayashi Hironori, Takamatsu Yuki, Bulut Haydar, Yedidi Ravikiran, Rao Kalapala, Ghosh Arun, Mitsuya Hiroaki

    Abstracts of Papers of the American Chemical Society　255　2018

  37. Raltegravir blocks the infectivity of red-fluorescent-protein (mCherry)-labeled HIV-1JR-FL in the setting of post-exposure prophylaxis in NOD/SCID/Jak3-/- mice transplanted with human PBMCs. International-journal Peer-reviewed

    Hiromi Ogata-Aoki, Nobuyo Higashi-Kuwata, Shin-Ichiro Hattori, Hironori Hayashi, Matthew Danish, Manabu Aoki, Chiemi Shiotsu, Yumi Hashiguchi, Akinobu Hamada, Hisataka Kobayashi, Hironobu Ihn, Seiji Okada, Hiroaki Mitsuya

    Antiviral research　149　78-88　2018/01

    DOI： 10.1016/j.antiviral.2017.09.003 　

    ISSN： 0166-3542

    More details Close

    Employing NOD/SCID/Jak3-/- mice transplanted with human PBMCs (hNOJ mice) and replication-competent, red-fluorescent-protein (mCherry; mC)-labeled HIV-1JR-FL (HIVmC), we examined whether early antiretroviral treatment blocked the establishment of HIV-1 infection. The use of hNOJ mice and HIVmC enabled us to visually locate infection foci and to examine the early dynamics of HIVmC infection without using a large amount of antiretroviral unlike in non-human primate models. Although when raltegravir (RAL) administration was begun 1 day after intraperitoneal (ip) inoculation of HIVmC, no plasma p24 or plasma HIV-1-RNA (pRNA) were detected in 10 of 12 hNOJ (hNOJmCRAL+) mice as assessed on the last day of the 14-day continuous twice-daily RAL administration, all 10 untreated hNOJmC (hNOJmCRAL-) mice became positive for p24 and pRNA and had significantly swollen lymph nodes in peritoneal cavity and abundant p24+/mC+/CD3+/CD4+ T cells and p24+/mC+/CD68+ monocytes/macrophages were identified in their omenta and mesenteric lymphoid tissues/lymph nodes upon necropsy of the mice on day 14. In 12 hNOJmCRAL+ mice, no significantly swollen lymph nodes were seen compared to hNOJmCRAL- mice; however, in the omentum of the 2 hNOJmCRAL+ mice that were positive for pRNA and in site RNA, mC+/p24+/CD3+/CD83+ cells were identified, suggesting that viral breakthrough occurred later in the observation period. The present data suggest that the use of hNOJ mouse model and HIVmC may shed light on the study of early-phase dynamics of HIV-1 infection and cellular events in post-exposure/pre-exposure prophylaxis.

  38. 網羅的Env標的阻害剤ライブラリーの構築(2) Peer-reviewed

    原田 恵嘉, 野村 渉, 鳴海 哲夫, 横山 勝, 前田 賢次, 林 宏典, 紺野 奇重, 引地 優太, 佐藤 裕徳, 玉村 啓和, 俣野 哲朗, 吉村 和久

    日本エイズ学会誌　19　(4)　401-401　2017/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  39. A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency Peer-reviewed

    Manabu Aoki, Hironori Hayashi, Kalapala Venkateswara Rao, Debananda Das, Nobuyo Higashi-Kuwata, Haydar Bulut, Hiromi Aoki-Ogata, Yuki Takamatsu, Ravikiran S. Yedidi, David A. Davis, Shin-ichiro Hattori, Noriko Nishida, Kazuya Hasegawa, Nobutoki Takamune, Prasanth R. Nyalapatla, Heather L. Osswald, Hirofumi Jono, Hideyuki Saito, Robert Yarchoan, Shogo Misumi, Arun K. Ghosh, Hiroaki Mitsuya

    ELIFE　6　2017/10

    DOI： 10.7554/eLife.28020 　

    ISSN： 2050-084X

  40. Early phase dynamics of traceable mCherry fluorescent protein-carrying HIV-1 infection in human peripheral blood mononuclear cells-transplanted NOD/SCID/Jak3-/- mice. International-journal Peer-reviewed

    Nobuyo Higashi-Kuwata, Hiromi Ogata-Aoki, Shin-Ichiro Hattori, Hironori Hayashi, Matthew Danish, Manabu Aoki, Chiemi Shiotsu, Tatsuyoshi Kawamura, Hironobu Ihn, Hisataka Kobayashi, Seiji Okada, Hiroaki Mitsuya

    Antiviral research　144　83-92　2017/08

    DOI： 10.1016/j.antiviral.2017.03.027 　

    ISSN： 0166-3542

    More details Close

    We attempted to elucidate early-phase dynamics of HIV-1 infection using replication-competent, red-fluorescent-protein (mCherry)-labeled HIV-1JR-FL (HIVJR-FLmC) and NOD/SCID/Jak3-/- mice transplanted with Individual-A's human peripheral blood mononuclear cells (hPBMC)(hNOJ mice). On day 7 following HIVJR-FLmC inoculation, mCherry-signal-emitting infection foci were readily identified in the subserosa of 10 of 10 HIVJR-FLmC-inoculated hNOJ mice, although infection foci were not located without the mCherry signal in unlabeled HIV-1JR-FL-inoculated mice (n = 6). Even on day 14, infection foci were hardly located in the unlabeled HIV-1JR-FL-inoculated mice, while in all of 7 HIVJR-FLmC-inoculated hNOJ mice examined, mCherry-signal-emitting lymph nodes were easily identified, in which active viral replication was present. On day 14, a significantly larger number of mesenteric lymph nodes were seen in HIVJR-FLmC-exposed hNOJ mice than in HIVJR-FLmC-unexposed mice (P = 0.0025). The weights of mesenteric lymph nodes of those HIVJR-FLmC-exposed hNOJ mice were also greater than those of HIVJR-FLmC-unexposed mice (P = 0.0005). When hNOJ mice were inoculated with HIVJR-FLmC-exposed hPBMC from Individual-B, significantly greater viremia was seen than in cell-free HIVJR-FLmC-inoculated hNOJ mice as examined on day 7. In the lymph nodes of those mice inoculated with HIVJR-FLmC-exposed hPBMC from Individual-B, a substantial number of Individual-B's HIVJR-FLmC-infected cells were identified together with Individual-A's cells as examined on day 14. The present HIVJR-FLmC-infected mouse model represents the first system reported using traceable HIVJR-FLmC and human target cells, not using SIV or simian cells, which should be of utility in studies of early-phases of HIV-1 transmission and in evaluating the effects of potential agents for post-exposure and pre-exposure prophylaxis.

  41. Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants Peer-reviewed

    Arun K. Ghosh, Kalapala Venkateswara Rao, Prasanth R. Nyalapatla, Heather L. Osswald, Cuthbert D. Martyr, Manabu Aoki, Hironori Hayashi, Johnson Agniswamy, Yuan-Fang Wang, Haydar Bulut, Debananda Das, Irene T. Weber, Hiroaki Mitsuya

    JOURNAL OF MEDICINAL CHEMISTRY　60　(10)　4267-4278　2017/05

    DOI： 10.1021/acs.jmedchem.7b00172 　

    ISSN： 0022-2623

    eISSN： 1520-4804

  42. Molecular simulation of EFdA and related analogs to determine the structural basis of HIV-1 drug resistance Peer-reviewed

    Das Debananda, Takamatsu Yuki, Kohgo Satoru, Hattori Shinichiro, Hayashi Hironori, Matsuda Kouki, Sarafianos Stefan, Mitsuya Hiroaki, Maeda Kenji

    Abstracts of Papers of the American Chemical Society　253　2017

  43. 網羅的Env標的阻害剤ライブラリーの構築(1) Peer-reviewed

    原田 恵嘉, 野村 渉, 鳴海 哲夫, 横山 勝, 前田 賢次, 林 宏典, 荻原 香澄, 石田 有佑, 引地 優太, 佐藤 裕徳, 玉村 啓和, 俣野 哲朗, 吉村 和久

    日本エイズ学会誌　18　(4)　514-514　2016/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  44. Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation Peer-reviewed

    Arun K. Ghosh, Heather L. Osswald, Kristof Glauninger, Johnson Agniswamy, Yuan-Fang Wang, Hironori Hayashi, Manabu Aoki, Irene T. Weber, Hiroaki Mitsuya

    JOURNAL OF MEDICINAL CHEMISTRY　59　(14)　6826-6837　2016/07

    DOI： 10.1021/acs.jmedchem.6b00639 　

    ISSN： 0022-2623

    eISSN： 1520-4804

  45. C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir Peer-reviewed

    Manabu Aoki, Hironori Hayashi, Ravikiran S. Yedidi, Cuthbert D. Martyr, Yuki Takamatsu, Hiromi Aoki-Ogata, Teruya Nakamura, Hirotomo Nakata, Debananda Das, Yuriko Yamagata, Arun K. Ghosh, Hiroaki Mitsuya

    JOURNAL OF VIROLOGY　90　(5)　2180-2194　2016/03

    DOI： 10.1128/JVI.01829-15 　

    ISSN： 0022-538X

    eISSN： 1098-5514

  46. Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein Ligand X-ray Studies Peer-reviewed

    Arun K. Ghosh, Cuthbert D. Martyr, Heather L. Osswald, Venkat Reddy Sheri, Luke A. Kassekert, Shujing Chen, Johnson Agniswamy, Yuan-Fang Wang, Hironori Hayashi, Manabu Aoki, Irene T. Weber, Hiroaki Mitsuya

    JOURNAL OF MEDICINAL CHEMISTRY　58　(17)　6994-7006　2015/09

    DOI： 10.1021/acs.jmedchem.5b00900 　

    ISSN： 0022-2623

    eISSN： 1520-4804

  47. Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir Peer-reviewed

    Hironori Hayashi, Nobutoki Takamune, Takashi Nirasawa, Manabu Aoki, Yoshihiko Morishita, Debananda Das, Yasuhiro Koh, Arun K. Ghosh, Shogo Misumi, Hiroaki Mitsuya

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　111　(33)　12234-12239　2014/08

    DOI： 10.1073/pnas.1400027111 　

    ISSN： 0027-8424

  48. A ribonucleopeptide module for effective conversion of an RNA aptamer to a fluorescent sensor Peer-reviewed

    Fong Fong Liew, Hironori Hayashi, Shun Nakano, Eiji Nakata, Takashi Morii

    BIOORGANIC & MEDICINAL CHEMISTRY　19　(19)　5771-5775　2011/10

    DOI： 10.1016/j.bmc.2011.08.031 　

    ISSN： 0968-0896

  49. Design Strategies of Fluorescent Biosensors Based on Biological Macromolecular Receptors Peer-reviewed

    Kazuki Tainaka, Reiko Sakaguchi, Hironori Hayashi, Shun Nakano, Fong Fong Liew, Takashi Morii

    SENSORS　10　(2)　1355-1376　2010/02

    DOI： 10.3390/s100201355 　

    ISSN： 1424-8220

    eISSN： 1424-8220

  50. Development of A Fluorescent Ribonucleopeptide Sensor for Histamine

    FUKUDA Masatora, HAYASHI Hironori, HASEGAWA Tetsuya, MORII Takashi

    Trans Mater Res Soc Jpn　34　(3)　525-527　2009/09

    Publisher: The Materials Research Society of Japan

    DOI： 10.14723/tmrsj.34.525 　

    ISSN： 1382-3469

    More details Close

    Biologically active amines play major roles in the regulation of movement and are implicated in the pathophysiology of Parkinson's and Huntington's diseases, psychosis, and drug addiction. Fluorescent biosensors based on the biological macromolecule receptor are useful tool for investigating the function of biologically active amines. Our strategy of the stepwise molding using a ribonucleopeptide (RNP) framework provides fluorescent biosensors with a variety of binding and optical characteristics for small molecules. Here we report fluorescent RNP sensors for histamine with a variety of binding and signal-transducing characteristics. Combination of RNA subunits of histamine-binding RNP receptors obtained by in vitro selection and a Rev peptide modified with 7-methoxycoumarin-3-carboxylic acid afforded a fluorescent RNP sensor with distinct signaling characteristics in the changes of fluorescence emission intensity upon binding to histamine. The fluorescent histamine sensor showed distinct selectivity for histamine over structurally related histamine analogs, such as imidazole, ethylamine and L-histidine.

  51. Structure-based design of fluorescent biosensors from ribonucleopeptide complexes. Peer-reviewed

    Hayashi H, Inoue M, Morii T

    Nucleic acids symposium series (2004)　(51)　95-96　2007

    DOI： 10.1093/nass/nrm048 　

  52. Construction of ribonucleopeptide-based fluorescent sensors for biologically active amines. Peer-reviewed

    Hasegawa T, Hayashi H, Morii T

    Nucleic acids symposium series (2004)　(51)　423-424　2007

    DOI： 10.1093/nass/nrm212 　

Show all ︎Show first 5

Misc. 58

  1. Structure-activity relationship studies of SARS-CoV-2 main protease inhibitors focused on fluorine substitutions

    山本龍星, 鍬田伸好, 辻耕平, 小早川拓也, 石井貴大, 篠原功紀, 服部真一郎, 岸本直樹, 高宗暢暁, 三隅将吾, BULUT Haydar, 林宏典, 満屋裕明, 満屋裕明, 玉村啓和

    日本薬学会年会要旨集(Web)　145th　2025

    ISSN： 0918-9823

  2. Development of a novel method to measure intraprotein interactions of rubella virus membrane fusion protein, E1

    鈴木聡志, 坂田真史, 中津祐一郎, 永井美智, 亀谷太一, 亀谷太一, 白井達也, 畑山靖佳, 西真由子, 横山勝, 水越文徳, 林宏典, 村山和隆, 森嘉生, 梁明秀, 梁明秀

    日本ウイルス学会学術集会プログラム・予稿集(Web)　72nd　2025

  3. 細胞内環境応答型新規人工核酸を活用した虚血性疾患選択的薬効発現触媒的核酸医薬法の開発

    藤田一寿, 堀内結翔, 松本光代, 松本光代, 稲垣雅仁, 林宏典, 林宏典, 荒木保幸, 西嶋政樹, 西嶋政樹, 児玉栄一, 児玉栄一, 和田健彦

    日本核酸医薬学会誌(Web)　28　(1)　2024

  4. Development of small molecule inhibitors with potent antiviral activity targeting SARS-CoV-2 main protease

    篠原功紀, 鍬田伸好, 辻耕平, 石井貴大, 小早川拓也, 服部真一朗, 岸本直樹, 高宗暢暁, 三隅将吾, HAYDAR Bulut, 林宏典, 満屋裕明, 満屋裕明, 玉村啓和

    日本薬学会年会要旨集(Web)　144th　2024

    ISSN： 0918-9823

  5. 抗SARS-CoV-2メインプロテアーゼ阻害剤の創薬研究開発

    鍬田 伸好, 辻 耕平, 林 宏典, 石井 貴大, 小早川 拓也, 中野 堅太, 服部 真一朗, 岸本 直樹, 高宗 暢暁, 青木 宏美, Bulut Haydar, Das Debananda, 今井 正樹, 木曽 真紀, 助永 義和, 高松 悠樹, 岡村 匡史, 三隅 将吾, 河岡 義裕, 玉村 啓和, 満屋 裕明

    日本エイズ学会誌　25　(4)　428-428　2023/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  6. 抗SARS-CoV-2メインプロテアーゼ阻害剤の創薬研究開発

    鍬田 伸好, 辻 耕平, 林 宏典, 石井 貴大, 小早川 拓也, 中野 堅太, 服部 真一朗, 岸本 直樹, 高宗 暢暁, 青木 宏美, Bulut Haydar, Das Debananda, 今井 正樹, 木曽 真紀, 助永 義和, 高松 悠樹, 岡村 匡史, 三隅 将吾, 河岡 義裕, 玉村 啓和, 満屋 裕明

    日本エイズ学会誌　25　(4)　428-428　2023/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  7. Development of novel protein-protein interaction inhibitors against respiratory syncytial virus

    鈴木聡志, 天野陽斗, 薄井友輔, 河治久実, 笹野美奈, 西山瑛絵, 平松佳樹, 橋本浩一, 村山和隆, 児玉栄一, 大石真也, 林宏典

    日本小児科学会雑誌　127　(2)　231-231　2023/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  8. Blocking protein-protein interactions are applicable to development of novel antiviral agents for SARS-CoV-2

    鈴木聡志, 黒田実央, 河治久実, 村山和隆, 林宏典, 大石真也, 児玉栄一

    日本小児科学会雑誌　127　(2)　235-235　2023/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  9. Design Strategy of DNA-Artificial Nucleic Acid Chimera Toward Enhancement of Target RNA Cleavage Activities:-Modification Effects of DNA Moiety upon Complex Stabilities and Activity-

    和田健彦, 藤田一寿, 石渡望, 林宏典, 荒木保幸, 西嶋政樹, 児玉栄一, 稲垣雅仁

    日本核酸医薬学会年会講演要旨集(CD-ROM)　8th　2023

  10. Novel Design Strategy of DNA-Artificial Nucleic Acid Chimera Toward Enhancement of Target RNA Cleavage Activities: Modification Effects of DNA Moiety upon Complex Stabilities and Activity

    石渡望, 稲垣雅仁, 西嶋政樹, 林宏典, 荒木保幸, 児玉栄一, 和田健彦

    日本化学会春季年会講演予稿集(Web)　103rd　2023

  11. Construction of Catalytic Target RNA Cleavage Function Installed Chimeric Artificial Nucleic Acids (CANA) toward Development of COVID-19 Treatments-I: Design, Synthesis, and in vitro Properties

    藤田一寿, 石渡望, 稲垣雅仁, 西嶋政樹, 林宏典, 三瓶悠, 荒木保幸, 山本剛史, 山吉麻子, 児玉栄一, 和田健彦

    日本化学会春季年会講演予稿集(Web)　103rd　2023

  12. フッ素化及びチオアミド置換を活用した新規SARS-CoV-2メインプロテアーゼ阻害剤の創製

    篠原功紀, 鍬田伸好, 辻耕平, 石井貴大, 小早川拓也, 服部真一朗, 岸本直樹, 高宗暢暁, 三隅将吾, BULUT Haydar, 林宏典, 満屋裕明, 満屋裕明, 玉村啓和

    日本薬学会関東支部大会講演要旨集(CD-ROM)　67th　2023

  13. Development of SARS-CoV-2 Main Protease Inhibitors by Fluorine Substitution and Amide Bond Conversion

    篠原功紀, 鍬田伸好, 辻耕平, 石井貴大, 小早川拓也, 服部真一朗, 岸本直樹, 高宗暢暁, 三隅将吾, BULUT Haydar, 林宏典, 満屋裕明, 満屋裕明, 玉村啓和

    日本薬学会年会要旨集(Web)　143rd　2023

    ISSN： 0918-9823

  14. 新規プロテアーゼ阻害剤GRL-142は、インテグラーゼのNLSに結合、HIV-1DNAの核移行を阻害し、インテグラーゼ阻害剤耐性HIV-1変異体を強力に阻害する

    青木 学, 青木 宏美, Bulut Haydar, 林 宏典, 長谷川 和也, Ghosh Arun, Pau Alice, 満屋 裕明

    日本エイズ学会誌　24　(4)　428-428　2022/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  15. Propose and demonstration of novel chimeric artificial nucleic acids strategy and investigation of RNase H mediated target RNA cleavage activity

    石渡望, 矢野輝, 稲垣雅仁, 西嶋政樹, 林宏典, 鈴木康弘, 荒木保幸, 児玉栄一, 佐藤靖史, 和田健彦

    日本化学会春季年会講演予稿集(Web)　102nd　2022

  16. 触媒的標的RNA切断を目指した新規キメラ人工核酸の設計・合成-DNA部位の修飾による活性効果-

    石渡望, 稲垣雅仁, 藤田一寿, 西嶋政樹, 林宏典, 荒木保幸, 児玉栄一, 和田健彦

    東北大学多元物質科学研究所研究発表会講演予稿集　22nd　2022

  17. Novel Design Strategy of DNA-Artificial Nucleic Acid Chimera Toward Enhancement of Target RNA Cleavage Activities: Application for COVID-19 Therapeutics

    石渡望, 藤田一寿, 堀内結翔, 林宏典, 稲垣雅仁, 稲垣雅仁, 西嶋政樹, 荒木保幸, 児玉栄一, 和田健彦

    日本核酸医薬学会年会講演要旨集(CD-ROM)　7th　2022

  18. Structure-based design and optimization of novel measles virus fusion inhibitors

    山口夕貴, 高原葵, 青木啓輔, 青木啓輔, 中津亨, 中津亨, 平田和成, 鈴木聡志, 林宏典, 河治久実, 井貫晋輔, 大野浩章, 加藤博章, 村山和隆, 児玉栄一, 大石真也, 大石真也

    メディシナルケミストリーシンポジウム講演要旨集　39th (CD-ROM)　2022

    ISSN： 0919-214X

  19. 新規フッ素化抗SARS-CoV-2メインプロテアーゼ阻害剤の開発

    鍬田伸好, 辻耕平, 林宏典, 石井貴大, 小早川拓也, 中野堅太, 服部真一朗, 岸本直樹, 高宗暢暁, 青木宏美, BULUT Haydar, DAS Debananda, 今井正樹, 今井正樹, 木曽真紀, 助永義和, 鈴木忠樹, 岡村匡史, 三隅将吾, 河岡義裕, 河岡義裕, 河岡義裕, 玉村啓和, 満屋裕明, 満屋裕明

    日本エイズ学会誌　24　(4)　2022

    ISSN： 1344-9478

  20. フルオロウラシル誘導体は新規作用機序であるピリミジン代謝阻害によって薬剤耐性グラム陽性球菌に優れた抗菌活性を示す

    大江 千紘, 林 宏典, 平田 和成, 勝見 真琴, 賀来 満夫, 児玉 栄一

    感染症学雑誌　94　(臨増)　301-301　2020/03

    Publisher: (一社)日本感染症学会

    ISSN： 0387-5911

    eISSN： 1884-569X

  21. Synthetic study on carbocyclic-2’-deoxynucleoside-synthesis of carbocyclic-2’-deoxy-7-deazaadenosine-

    水石彩菜, 斎藤智亜季, 目黒公太郎, 植松明星, 原島利彰, 林宏典, 児玉栄一, 三澤隆史, 出水庸介, 栗原正明, 紺野奇重

    日本薬学会年会要旨集(CD-ROM)　140th (Web)　2020

    ISSN： 0918-9823

  22. Synthetic study on carbocyclic-2’-deoxynucleoside-synthesis of carbocyclic-2’-deoxyuridine

    斎藤智亜季, 水石彩菜, 目黒公太郎, 植松明星, 原島利彰, 林宏典, 児玉栄一, 三澤隆史, 出水庸介, 栗原正明, 紺野奇重

    日本薬学会年会要旨集(CD-ROM)　140th (Web)　2020

    ISSN： 0918-9823

  23. HIVプロテアーゼ阻害剤GRL-142とその誘導体の強力な抗ウイルス活性発揮機序の解明

    服部 真一朗, Bulut Haydar, 林 宏典, 青木 学, 青木 宏美, 長谷川 和長, Ghosh Arun K., 満屋 裕明

    日本エイズ学会誌　21　(4)　427-427　2019/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  24. P2-bis-THF基およびP2'-CpAbt基を有し、多剤耐性HIV変異株に対しても強力な抗ウイルス活性を発揮する新規プロテアーゼ阻害薬の同定

    高松 悠樹, 青木 学, Bulut Haydar, Das Debananda, 天野 将之, Sheri Venkata Reddy, Kovari Ladislau C., 林 宏典, Delino Nicole S., Ghosh Arun K., 満屋 裕明

    日本エイズ学会誌　21　(4)　428-428　2019/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  25. 麻疹ウイルス膜融合阻害ペプチドの最小活性配列の同定と相互作用解析

    高原葵, 中津亨, 平田和成, 林宏典, 河治久実, 井貫晋輔, 大野浩章, 加藤博章, 児玉栄一, 大石真也

    メディシナルケミストリーシンポジウム講演要旨集　37th　2019

    ISSN： 0919-214X

  26. 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　2018/11

    Publisher: (株)近代出版

    ISSN： 0910-7029

  27. 極めて強力な抗HIV活性を発揮する新規プロテアーゼ阻害剤GRL-142/KU-241の同定及びそのSIVmac251感染サルにおける抗ウイルス効果

    鍬田伸好, 青木学, 青木学, KULKARNI Viraj, 服部真一朗, 青木宏美, 林宏典, 城野博史, 山川佑可子, 前田賢次, 刈谷龍昇, 岡田誠治, GHOSH Arun K., RUPRECHT Ruth M., 満屋裕明, 満屋裕明, 満屋裕明

    日本エイズ学会誌　20　(4)　2018

    ISSN： 1344-9478

  28. 極めて強力な抗ウイルス活性を発揮する新規HIVプロテアーゼ阻害剤の同定とその機序

    服部真一朗, 林宏典, BULUT Haydar, 長谷川和也, 青木学, GHOSH Arun K., 満屋裕明, 満屋裕明, 満屋裕明

    日本エイズ学会誌　20　(4)　2018

    ISSN： 1344-9478

  29. 変異HIV-RT(Q151M)と抗HBV薬entecavirの活性と結晶構造を基盤としたHIV-RTとHBV-RTの構造学的検討

    前田 賢次, 安武 義晃, 田村 範子, 服部 真一朗, 林 宏典, 松田 幸樹, 高松 悠樹, 向後 悟, 満屋 裕明

    日本エイズ学会誌　19　(4)　402-402　2017/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  30. 多剤耐性HIV変異株にも強力な抗ウイルス活性を発揮する新規HIVプロテアーゼ阻害剤の同定

    服部真一朗, 林宏典, 青木学, 長谷川和也, BULUT Haydar, DAS Debananda, 前田賢次, GHOSH Arun, 満屋裕明, 満屋裕明, 満屋裕明

    日本エイズ学会誌　19　(4)　2017

    ISSN： 1344-9478

  31. Crystal structures of HIV-1 reverse transcriptase mutants complexed with DNA aptamer

    安武義晃, 田村範子, 服部真一朗, 林宏典, 松田幸樹, 前田賢次, 満屋裕明, 満屋裕明

    量子ビームサイエンスフェスタ(Web)　2016　2017

  32. Elucidation of the Mechanism of HIV-1 Protease Dimerization and Its Inhibition by HIV-1 Protease Inhibitors

    19　(3)　128-136　2017

    Publisher: 日本エイズ学会

    ISSN： 1344-9478

  33. 日本の研究室から HIV-1プロテアーゼの二量体化阻害メカニズム

    林 宏典, 満屋 裕明

    HIV感染症とAIDSの治療　8　(1)　68-75　2017

    Publisher: メディカルレビュー社

    ISSN： 2185-1689

  34. 改変HIV逆転写酵素とDNAアプタマー複合体の結晶解析

    安武義晃, 田村範子, 林宏典, 前田賢次

    KEK Progress Report (Web)　(2017-10)　ROMBUNNO.207 (WEB ONLY)　2017

    ISSN： 1344-6320

  35. 表面プラズモン共鳴法を用いた新規HIV-1侵入阻害剤活性評価法の樹立

    松田 幸樹, 林 宏典, 原田 恵嘉, 服部 真一朗, 鳴海 哲夫, 玉村 啓和, 吉村 和久, 満屋 裕明, 前田 賢次

    日本エイズ学会誌　18　(4)　523-523　2016/11

    Publisher: (一社)日本エイズ学会

    ISSN： 1344-9478

  36. 逆転写酵素阻害剤EFdA(MK-8591)に対する薬剤耐性機序の構造学的解析と耐性株に有効な新規薬剤の設計・開発

    前田賢次, 高松悠樹, 向後悟, 向後悟, 服部真一朗, 鍬田伸好, 林宏典, DEBANANDA Das, 満屋裕明, 満屋裕明, 満屋裕明

    日本エイズ学会誌　18　(4)　2016

    ISSN： 1344-9478

  37. DRV耐性株を含む種々の多剤耐性変異株にも有効な新規抗HIV薬候補化合物KU-241の体内動態・脳組織内濃度・2週間反復投与毒性

    鍬田伸好, 青木学, 青木学, 青木学, 服部真一朗, 青木宏美, 青木宏美, 林宏典, 林宏典, 林宏典, 前田賢次, GHOSH Arun K., 満屋裕明, 満屋裕明, 満屋裕明

    日本エイズ学会誌　18　(4)　2016

    ISSN： 1344-9478

  38. KU-241が前例を見ない程強力な抗HIV作用を発揮する機序の解析

    林宏典, 青木学, DAS Debananda, 服部真一朗, 青木宏美, 鍬田伸好, 高松悠樹, RAVIKIRAN Yedidi, 長谷川和也, GHOSH Arun K, 満屋裕明, 満屋裕明, 満屋裕明

    日本エイズ学会誌　18　(4)　2016

    ISSN： 1344-9478

  39. 極めて強力な抗HIV活性を有する新規HIV-1プロテアーゼ阻害剤,KU-241

    服部真一朗, 青木学, 青木学, 鍬田伸好, 林宏典, 青木宏美, GHOSH Arun K, 前田賢次, 満屋裕明, 満屋裕明

    日本エイズ学会誌　18　(4)　2016

    ISSN： 1344-9478

  40. HIV-1の高度darunavir耐性発現にはdarunavir高感受性を単独で付与するV321の獲得が重要である

    青木学, 青木学, DAS Debananda, 林宏典, 青木宏美, GHOSH Arun K., 満屋裕明, 満屋裕明

    日本エイズ学会誌　16　(4)　2014

    ISSN： 1344-9478

  41. HIV-1プロテアーゼ(PR)の二量体化は2ステップで起こりdarunavirのPR二量体化阻害は最初のステップで起こる

    林宏典, 林宏典, 高宗暢暁, 韮澤崇, 青木学, 青木学, 森下宜彦, DAS Debananda, こう康博, 三隅将吾, 満屋裕明, 満屋裕明

    日本エイズ学会誌　16　(4)　2014

    ISSN： 1344-9478

  42. HIVのDRV耐性獲得機構の解明

    林宏典, 青木学, DAS Debananda, YEDIDI Ravikiran S., 中村照也, 高宗暢暁, 中田浩智, コウ康博, 三隅将吾, 山縣ゆり子, 満屋裕明, 満屋裕明

    日本エイズ学会誌　15　(4)　2013

    ISSN： 1344-9478

  43. 新規プロテアーゼ阻害剤GRL-015,-085,-097は,プロテアーゼD29,D30,G48の主鎖と重要な水素結合を形成,多剤耐性HIV-1変異体に強力な活性を発揮する

    青木学, 青木学, 林宏典, YEDIDI Ravikiran S., DAS Debananda, 青木宏美, MARTYR Cuthbert D, GHOSH Arun K., 満屋裕明, 満屋裕明

    日本エイズ学会誌　15　(4)　2013

    ISSN： 1344-9478

  44. HIV曝露後早期における抗HIV剤投与効果の解析

    青木宏美, 鍬田伸好, 服部真一朗, 林宏典, MOORE Amber R., 青木学, 岡田誠治, 満屋裕明, 満屋裕明

    日本エイズ学会誌　15　(4)　2013

    ISSN： 1344-9478

  45. HIV-1 (特集 抗菌薬と抗ウイルス薬 : 正しい使い方) -- (抗ウイルス薬治療の実際)

    林 宏典, 満屋 裕明

    臨牀と研究　89　(10)　1362-1368　2012/10

    Publisher: 大道学館出版部

    ISSN： 0021-4965

  46. DRV耐性HIV-1変異株にも強力な活性を発揮する新規プロテアーゼ阻害剤GRL-015-11A,GRL-085-11A,GRL-097-11Aの抗HIV-1活性の検討

    青木学, 青木学, 林宏典, 青木宏美, CUTHBERT D. Martyr, ARUN K. Ghosh, 満屋裕明, 満屋裕明

    日本エイズ学会誌　14　(4)　2012

    ISSN： 1344-9478

  47. 抗HIV剤raltegravirによるHIV体内播種早期ダイナミクスの変容

    鍬田伸好, 青木宏美, 服部真一郎, 林宏典, MOORE Amber, 青木学, 青木学, 岡田誠治, 満屋裕明, 満屋裕明

    日本エイズ学会誌　14　(4)　2012

    ISSN： 1344-9478

  48. HIVプロテアーゼ二量体化及びdarunavirの二量体化阻害メカニズムの解明

    林宏典, 高宗暢暁, 青木学, 青木学, 三隅将吾, 満屋裕明, 満屋裕明

    日本エイズ学会誌　14　(4)　2012

    ISSN： 1344-9478

  49. 蛍光蛋白質ラベル化HIVの分子基盤解析

    林宏典, 青木宏美, 鍬田伸好, 満屋裕明

    日本エイズ学会誌　13　(4)　2011

    ISSN： 1344-9478

  50. mCherry可視化HIVを用いたHIV体内播種早期ダイナミクスと抗HIV剤によるその変容の検討-2

    鍬田伸好, 青木宏美, 服部真一郎, 林宏典, 青木学, 青木学, 中村太平, 岡田誠治, 満屋裕明, 満屋裕明

    日本エイズ学会誌　13　(4)　2011

    ISSN： 1344-9478

  51. Tipranavirの酵素活性阻止能とプロテアーゼ二量体化阻止能の喪失に関与するアミノ酸変異の同定

    青木学, 青木学, 井手一彦, DANISH Matthew, 青木宏美, 林宏典, 満屋裕明, 満屋裕明

    日本エイズ学会誌　13　(4)　2011

    ISSN： 1344-9478

  52. mCherry可視化HIVを用いたHIV体内播種早期ダイナミクスと抗HIV剤によるその変容の検討-1

    青木宏美, 鍬田伸好, 服部真一郎, 林宏典, 青木学, 岡田誠治, 満屋裕明, 満屋裕明

    日本エイズ学会誌　13　(4)　2011

    ISSN： 1344-9478

  53. mCherry可視化HIV-1を用いたHIV-1体内播種早期ダイナミクスの検討:2

    青木宏美, 鍬田伸好, 服部真一郎, 林宏典, 青木学, 青木学, 前田賢次, 岡田誠治, 満屋裕明, 満屋裕明

    日本エイズ学会誌　12　(4)　2010

    ISSN： 1344-9478

  54. リボヌクレオペプチドATPセンサーの構造特性

    林宏典, 井上雅文, 森井孝, 森井孝

    日本化学会講演予稿集　87th　(2)　2007

    ISSN： 0285-7626

  55. リボヌクレオペプチド蛍光センサーの合目的設計

    林宏典, 井上雅文, 森井孝

    生体機能関連化学シンポジウム講演要旨集　22nd　2007

  56. リボヌクレオペプチドATPリセプターの高次構造解析

    井上雅文, 林宏典, 森井孝, 森井孝

    日本化学会講演予稿集　87th　(2)　2007

    ISSN： 0285-7626

  57. リボヌクレオペプチドを用いた蛍光性バイオセンサーの設計

    林宏典, 井上雅史, 森井孝

    日本RNA学会年会要旨集　9th　2007

  58. Ribonucleopeptide receptors targeting histamine

    林宏典, 森井孝, 森井孝

    日本化学会講演予稿集　86th　(2)　2006

    ISSN： 0285-7626

Show all ︎Show first 5

Books and Other Publications 4

  1. 臨床と微生物

    児玉 栄一, 林 宏典, 臼井 恵美子

    近代出版　2018/11

  2. HIV感染症とAIDSの治療

    林 宏典

    株式会社メディカルレビュー社　2017

  3. 臨床と研究臨床と研究

    林 宏典

    大同学館出版　2012

  4. Combinatorial Methods for Chemical and Biological Sensors

    Fukuda M, Hasegawa T, Hayashi H and Morii T.

    Supringer　2008

    ISBN: 9780387737126

Presentations 1

  1. Efforts to develop drugs to reduce the risk of emerging and re-emerging infectious diseases International-presentation

    Hironori Hayashi

    Japan-US Research Collaboration Week　2025/07/28

Industrial Property Rights 1

  1. AGENTS FOR CONVERTING CARBAPENEM-RESISTANT BACTERIA TO CARBAPENEM-SUSCEPTIBLE BACTERIA, AND USE THEREOF

    Hironori Hayashi

    Property Type: Patent

Research Projects 12

  1. 高活性触媒的標的RNA切断機能付与型人工核酸の構築と革新的治療基盤としての展開

    和田健彦, 児玉栄一, 稲垣雅仁, 荒木保幸, 西嶋政樹, 林宏典

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(S)

    Category: 基盤研究(S)

    Institution: 東北大学

    2023/04 - 2028/03

  2. 高活性触媒的標的RNA切断機能付与型人工核酸の構築と新興感染症等治療基盤の創製

    和田 健彦, 林 宏典, 児玉 栄一, 稲垣 雅仁, 西嶋 政樹, 荒木 保幸

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(A)

    Institution: 東北大学

    2023/04/01 - 2026/03/31

  3. Development of novel antibacterial agents using crystal structure-based drug screening

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  4. 非天然型複合体を促進する化合物の合理的設計法開発

    林宏典 辻耕平

    Offer Organization: 国立研究開発法人日本医療研究開発機構

    System: 創薬基盤推進研究事業

    Institution: 国立大学法人東北大学

    2023/04 - 2026/03

  5. 新規SARS-CoV-2 Mpro阻害剤TKB245の臨床応用を前提とした非臨床試験

    Offer Organization: 国立研究開発法人日本医療研究開発機構

    System: 新興・再興感染症に対する革新的医薬品等開発推進研究事業

    Institution: 国立研究開発法人国立国際医療研究センター

    2022/04 - 2023/03

  6. 構造解析・生物進化学による学際融合は、迅速かつ有効なぺプチドPPI創製に有用である

    Offer Organization: 国立研究開発法人日本医療研究開発機構

    System: 創薬基盤推進研究事業

    Institution: 国立大学法人東北大学

    2020/04 - 2023/03

  7. Development of therapeutics for intractable infections using diverse natural products combined with stress-inductive biosynthesis and chemical modification

    Kodama Eiichi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2019/04/01 - 2022/03/31

    More details Close

    Molecular and structural diversities of natural compound have been required to expand for drug development. Here, we produced novel natural derivatives by the biosynthetic pathway remodeled by genome mining technology and identified novel anti-HIV agent. We established a simple and rapid screening method to develop antiviral agents against adenovirus, which caused epidemic keratoconjunctivitis. Additionally, we also identified several novel classes of antibacterial agents, which blocked uridine kinase, thymidine synthetase and serine hydroxymethyl transferase. Moreover, anti-viral and -bacterial mechanisms of compounds we identified were analyzed by time-of-addition method and crystal structural analysis. These results are important not only to expand molecular and structural diversities of natural compounds but also to develop therapeutic agents against antimicrobial resistances, unpredictable outbreaks and wildly destructive health consequences.

  8. 新規高活性触媒機能付与型核酸医薬によるCOVID-19感染症治療用創薬技術の開発

    Offer Organization: 国立研究開発法人日本医療研究開発機構

    System: 新興・再興感染症に対する革新的医薬品等開発推進研究事業

    Institution: 国立大学法人東北大学

    2021/04 - 2022/03

  9. Development of cross-virus drugs using norovirus as a model

    hayashi hironori

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Early-Career Scientists

    Institution: Tohoku University

    2019/04/01 - 2021/03/31

    More details Close

    As novel coronavirus (SARS-CoV-2) showed, viruses acquiring high infectivity between humans cause global pandemic and threaten not only the life but also economy, social and cultural activity of human. To take measure these pandemics, the research platform, which enable to promptly develop the therapeutic agents, is indispensable. This research focused on common points among viruses belonging different species. Norovirus (NoV) and SARS-CoV-2 need 3C-like protease (3CL-Pro) cording their genomic DNA to replicate in host cells. To develop anti-NoV and anti-SARS-CoV-2 agents, we targeted 3CL-Pro and make crystals, which were constructed with complex of novel compound and 3CL-Pro of SARS-CoV-2 (Mpro). The results of 3D structural analysis showed interaction way between the compound and Mpro. Additionally, the plasmid coding NoV 3CL-Pro was constructed for protein expression and crystallization. These results would contribute to develop anti-SARS-CoV-2 and anti-NoV agents.

  10. The study for elucidating the mechanisms of HIV-1's EFdA resistance. Competitive

    Hayashi Hironori

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    2017/04/01 - 2019/03/31

    More details Close

    EFdA was developed as a HIV-1 reverse transcriptase (RT) inhibitor and has been under the clinical trial. In this study, we purified the reverse transcriptase from EFdA resistant HIV-1 variants (RT-EFdA-R) and screened the crystallization conditions. Additionally, we employed the analysis by molecular dynamics to determine the EFdA resistant mechanisms of RT. As the result, an amino acid mutation (M184V) would decreas Van der Waals (VdW) interactions between EFdA and RT-EFdA-R. Thus, the M184V would decrease binding affinity of EFdA. However, EFdA keep strong interactions with F160, which is an amino acid locating at the cavity close to the active center of RT with and without M184V substitution. Notably, the introduction of amino acid mutation, F160A, eliminate growth ability of HIV-1. Thus, HIV-1 hardly introduced the mutation. This was the reason for the high genetic barrier of EFdA. These data shed light on developing the novel RT inhibitors.

  11. 多剤耐性HIV変異株に強力で高いCNS透過性を有する新規抗HIV薬の 開発と実用化 Competitive

    満屋 祐明

    Offer Organization: 日本医療研究開発機構

    System: エイズ対策実用化研究事業

    2015/04 - 2018/03

  12. 熱安定性の高いRNAとタンパク質の複合体の創製

    林 宏典

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特別研究員奨励費

    Category: 特別研究員奨励費

    Institution: 京都大学

    2009 - 2010

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    本研究では複合体の結晶構造及びRNAとの相互作用形式が解明されており、尚かつ80℃以上で生育可能な超好熱菌内において機能するH/ACA Box RNPを基に設計した基本骨格を用いて、望みの機能を有し熱安定性の高い機能性RNPを構築する方法論の開発を試みている。本年度は、(1)基本骨格として用いるRNA部位及びタンパク質部位の決定と、(2)超好熱菌のタンパク質の発現、精製法及び分子設計によるapADHの機能改変について学ぶ事を目的に研究を行った。 (1)RNA部位及びタンパク質部位の決定 H/ACA Box RNPを構成している1つのRNA(guide RNA)及び4つのタンパク質サブユニット(Cbf5,Nop10,L7Ae,Gar1)の内から基本骨格として用いる部位の選択を行った。タンパク質サブユニットに関しては、論文及び結晶構造を基にRNAと最も相互作用面が大きいCbf5及び最もアミノ酸数が少なくH/ACA Box RNPの構造変化に寄与すると考えられるNop10をタンパク質サブユニットとして選択した。guide RNAに関しては、論文を基にCbf5及びNop10との相互作用部位の確認を行いCbf5及びNop10との相互作用を保持した最小限のRNA単位及びランダム領域の導入箇所を決定した。 (2)超好熱菌由来のタンパク質の発現、精製法及び機能改変について 超好熱菌由来のタンパク質の発現、精製法及び機能改変について学ぶ為に超好熱菌由来のアルコールデヒドロゲナーゼ(apADH)を用いて超好熱菌由来タンパク質の発現及び精製を行い、更にモデリングソフトを用いた分子設計によりapADHを熱安定性の高いホルムアルデヒドジスムターゼ(FDM)に機能改変する事を試みた。超高熱菌の精製法の習得、8種類のapADH変異体の作製及び熱安定性の評価を行った。

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Teaching Experience 2

  1. Human Security and Infectious Disease/Advanced Infectious Disease　Tohoku University

  2. Health and Social Resilience for Large-scale Disaster　Tohoku University