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

• Project/Area Number: 24659484
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto 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
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• 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 / HIVプロテアーゼ / 新規薬剤開発

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

• [Journal Article] GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 Variants In Vitro, Antimicrob (2013)
  • Author(s): Amano M, Tojo Y, Gomez PMS, Campbell JR, Das D, Aoki M, Xu CX, Rao KV, Ghosh AK, and Mitsuya H
  • Journal Title: Agents Chemother Volume: 57 Issue: 5 Pages: 2036-2046
  • 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 the Protease Dimerization Inhibition Activity of Tipranavir (TPV) and Its Association with the Acquisition of Resistance to TPV by HIV- 1 (2012)
  • Author(s): Manabu Aoki, Matthew L. Danish, Hiromi Aoki- Ogata, Masayuki Amano, Kazuhiko Ide, Debananda Das, Yasuhiro Koh, and Hiroaki Mitsuya
  • Journal Title: Journal of Virology Volume: 86 Issue: 24 Pages: 13384-13396
  • 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 Issue: 9 Pages: 4707-4712
  • DOI: 10.1128/aac.00723-12
  • Peer Reviewed
• [Journal Article] CCR5 inhibitors:emergence, success, and challenges (2012)
  • Author(s): Maeda, K., Das, D. Nakata, H., andMitsuya, H
  • Journal Title: Expert Opin Emerging Drugs Volume: 17 Issue: 2 Pages: 135-145
  • 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 Issue: 1 Pages: 125-133
  • DOI: 10.1124/mol.112.078758
  • Peer Reviewed
• [Journal Article] Substituent effects on P2-cyclopentyltetrahydrofuranyl urethanes : Design, synthesis, and X- ray studies of potent HIV- 1 protease inhibitors (2012)
  • Author(s): Ghosh AK, Chapsal BD, Steffey M, Agniswamy J, Wang YF, Amano M, Weber IT, Mitsuya H
  • Journal Title: Bioorganic &Medicinal Chemistry Letters Volume: 22 Issue: 6 Pages: 2308-2311
  • DOI: 10.1016/j.bmcl.2012.01.061
  • Peer Reviewed
• [Journal Article] Enhancing protein backbone binding- -a fruitful concept for combating drugresistant HIV (2012)
  • Author(s): Ghosh AK, Anderson DD, Weber IT, Mitsuya H
  • Journal Title: Angewandte Chemie International Edition in English Volume: 51 Issue: 8 Pages: 1778-1802
  • 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 toxicity (2012)
  • 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 Issue: 3 Pages: 1630-1634
  • DOI: 10.1128/aac.05729-11
  • Peer Reviewed
• [Journal Article] Biochemical, inhibition, and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase. (2012)
  • Author(s): Tanyaradzwa P. Ei-Ichi Kodama, et al.
  • Journal Title: Nucleic Acids Research Volume: 40 Issue: 1 Pages: 345-359
  • 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)
• [Presentation] Thebinding properties of darunavir toHIV-1 protease monomer subunit (2012)
  • 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)
• [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)
• [Presentation] The binding properties of darunavir to HIV-1 protease monomer subunit. (2012)
  • Author(s): Hironori Hayashi, Nobutoki Takamune, Manabu Aoki, Yasuhiro Koh, Shogo Misumi & (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、阿蘇グランヴィリオホテル
• [Presentation] Binding properties of darunavir to the HIV-1 protease monomer subunit. (2012)
  • Author(s): Hironori Hayashi, Nobutoki Takamune, Manabu Aoki, Yasuhiro Koh, Shogo Misumi & (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、阿蘇グランヴィリオホテル
• [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
• [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
• [Book] Development of the first AIDSdrugs: AZT and other dideoxynucleosides.In Human Immunodeficiency Virus ReverseTranscriptase (2013)
  • 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