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2012 Fiscal Year Final Research Report

The analysis of HIV-protease dimerization mechanism at atomic andmolecular resolution, and the design of novel dimerization inhibition compounds.

Research Project

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Project/Area Number 24659484
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Infectious disease medicine
Research InstitutionKumamoto University

Principal Investigator

MITSUYA Hiroaki  熊本大学, 大学院・生命科学研究部, 教授 (20136724)

Project Period (FY) 2012
Keywords新規抗 HIV 剤開発 / プロテアーゼ / 二量体化阻害 / 結晶構造解析 / ESI-MS
Research Abstract

Using mass spectrometry and X-ray crystal structure analysis, we attempted toelucidate the dimerization dynamics of HIV -1 protease (PR). Our data showed that darunavir (DR V), anFDA-approved PR inhibitor, binds to both monomers and dimers of PR and blocks HIV -1 replication.We also showed that the introduction of DR V -resistance-associated amino acids into PR prevented DR Vfrom binding to PR monomers and decreased the amount of dimerized PR species. The data should be ofutility in not only examining the PR dimerization dynamics but also designing more potent PR inhibitorsthat hardly permit the emergence of DR V -resistant HIV -1 variants.

  • Research Products

    (14 results)

All 2013 2012

All Journal Article (10 results) (of which Peer Reviewed: 10 results) Presentation (3 results) Book (1 results)

  • [Journal Article] GRL-0519, anovel oxatricyclic-ligand-containingnonpeptidic HIV-1 protease inhibitor(PI), potently suppresses thereplication of a wide spectrum ofmulti-pi-resistant HIV-1 variants invitro2013

    • Author(s)
      Amano, M.,Tojo, Y., Salcedo-Gomez,Pedro.M., Campbell, J.R.,Das, D.,Aoki, M., Xu, C-X, Rao. K.V., Ghosh,A.K., and Mitsuya, H
    • Journal Title

      Antimicrob. Agents Chemother

      Volume: 57 Pages: 2036-46

    • DOI

      DOI:10.1128/AAC.02189-12

    • Peer Reviewed
  • [Journal Article] Effect oftranslocation defective reversetranscriptase inhibitors on theactivity of n348i, a connectionsubdomain drug resistant HIV-1 reversetranscriptase mutant.2012

    • Author(s)
      Michailidis E, Singh K, Ryan EM,Hachiya A, Ong YT, Kirby KA, MarchandB, Kodama EN, Mitsuya H, Parniak MA,Sarafianos SG
    • Journal Title

      Cell. Mol. Biol

      Volume: 58 Pages: 187-195

    • URL

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3551986/

    • Peer Reviewed
  • [Journal Article] Loss of protease dimerizationinhibition activity of tipranavir(TPV) is associated with HIV-1acquisition of resistance to TPV2012

    • Author(s)
      Aoki, M., Danish, M.L., Aoki-Ogata, H.,Amano, H., Ide, K., Koh, Y, and Mitsuya,H.
    • Journal Title

      J.Virol

      Volume: 86 Pages: 13384-13396

    • DOI

      DOI: 10.1128/JVI.07234-11

    • Peer Reviewed
  • [Journal Article] Response of simianimmunodeficiency virus to the novelnucleoside reverse transcriptaseinhibitor4'-ethynyl-2-fluoro-2'-deoxyadenosine in vitro and in vivo.2012

    • Author(s)
      Murphey-Corb, M., Rajakuma, P.,Michael., H., Nyaundi, J., Didier,P.J., Reeve, A.B., Mitsuya, H.,Sarafianos, S.G., and Parniak MA
    • Journal Title

      AntimicrobAgents Chemother.

      Volume: 56 Pages: 4707-4712

    • DOI

      DOI:10.1128/AAC.00723-12

    • Peer Reviewed
  • [Journal Article] CCR5 inhibitors:emergence, success, and challenges2012

    • Author(s)
      Maeda, K., Das, D. Nakata, H., andMitsuya, H
    • Journal Title

      Expert Opin Emerging Drugs

      Volume: 17 Pages: 135-145

    • DOI

      DOI:10.1517/14728214.2012.673584

    • Peer Reviewed
  • [Journal Article] Balancing antiviralpotency and host toxicity: identifyinga nucleotide inhibitor with an optimalkinetic phenotype for HIV-1 reversetranscriptase.2012

    • Author(s)
      Sohl, C.D., Kasiviswanathan, R., Kim,J., Pradere, U., Schinazi, R.F.,Copeland, W.C., Mitsuya, H., Baba, M.,Anderson, K.S.
    • Journal Title

      Mol Pharmacol

      Volume: 82 Pages: 125-133

    • DOI

      DOI:10.1124/mol.112.078758

    • Peer Reviewed
  • [Journal Article] Substituent effects onP2-cyclopentyltetrahydro- furanylurethanes: design, synthesis, andX-ray studies of potent HIV-1 proteaseinhibitors2012

    • Author(s)
      Ghosh, A.K., Chapsal, B.D., Steffey,M., Agniswamy, J., Wang, Y.F., Amano,M., Weber, I.T., Mitsuya, H
    • Journal Title

      Bioorg Med Chem Lett

      Volume: 22 Pages: 2308-2311

    • DOI

      DOI:10.1016/j.bmcl.2012.01.061

    • Peer Reviewed
  • [Journal Article] Enhancing proteinbackbone binding--a fruitful conceptfor combating drug-resistant HIV2012

    • Author(s)
      Ghosh AK, Anderson DD, Weber IT,Mitsuya H
    • Journal Title

      Angew Chem Int Ed Engl

      Volume: 51 Pages: 1778-1802

    • DOI

      DOI:10.1002/anie.201102762

    • Peer Reviewed
  • [Journal Article] Mechanism of interaction of humanmitochondrial DNA polymerase γ withthe novel nucleoside reversetranscriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine indicates alow potential for host toxicity2012

    • Author(s)
      Sohl, C.D., Singh, K., Kasiviswanathan,R., Copeland, W.C., Mitsuya, H.,Sarafianos, S.G., Anderson, K.S
    • Journal Title

      Antimicrob Agents Chemother

      Volume: 56 Pages: 1630-1634

    • DOI

      DOI:10.1128/AAC.05729-11

    • Peer Reviewed
  • [Journal Article] Biochemical,inhibition and inhibitor resistancestudies of xenotropic murine leukemiavirus-related virus reversetranscriptase.2012

    • Author(s)
      Ndongwe TP, Adedeji AO, Michailidis E, Ong YT, Hachiya A, Marchand B, Ryan EM, Rai DK, Kirby KA, Whatley AS, Burke DH, Johnson M, Ding S, Zheng YM, Liu SL, Kodama E, Delviks-Frankenberry KA, Pathak VK, Mitsuya H, Parniak MA, Singh K, Sarafianos SG
    • Journal Title

      Nucleic Acids Res

      Volume: 40 Pages: 345-359

    • DOI

      DOI:10.1093/nar/gkr694

    • Peer Reviewed
  • [Presentation] HIV プロテアーゼ二量体化機構及び darunavir の二量体化阻害メカニズムの解明2012

    • Author(s)
      林 宏典, 高宗 暢暁, 三隅 将吾, 青木学, 満屋 裕明
    • Organizer
      第26回 エイズ学会学術集会・総会
    • Place of Presentation
      慶應義塾大学 日吉キャンパス(神奈川)
    • Year and Date
      20121124-26
  • [Presentation] Thebinding properties of darunavir toHIV-1 protease monomer subunit2012

    • Author(s)
      Hironori Hayashi, Nobutoki Takamune,Manabu Aoki, Yasuhiro Koh, ShogoMisumi and Hiroaki Mitsuya
    • Organizer
      第13回熊本エイズセミナー・グローバルCOE 合同シンポジウム
    • Place of Presentation
      ホテル日航熊本(熊本)
    • Year and Date
      20121024-26
  • [Presentation] HIV プロテアーゼ二量体化機構及び DRV の二量体化阻害メカニズムの解明2012

    • Author(s)
      林 宏典, 高宗 暢暁, 三隅 将吾, 青木学, 満屋 裕明
    • Organizer
      第14回 白馬シンポジウム
    • Place of Presentation
      京都市国際交流会館(京都)
    • Year and Date
      20120607-08
  • [Book] Development of the first AIDSdrugs: AZT and other dideoxynucleosides.In Human Immunodeficiency Virus ReverseTranscriptase2013

    • Author(s)
      Yarchoan, R. and Mitsuya, H., A
    • Publisher
      Bench-to-Bedside Success (S.F.J. Le Griceand M. Goette, eds.), Springer Publishing,New York

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Published: 2014-08-29   Modified: 2014-10-21  

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