Mechanism of spontaneous degradation observed in the insertioncontaining HIV-1 Capsid proteins

2012 Fiscal Year Final Research Report

• Project/Area Number: 23791140
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: AMANO Masayuki 熊本大学, エイズ学研究センター・gCOEリサーチ, アソシエイト (30575080)
• Project Period (FY): 2011 – 2012
• Keywords: HIV-1 / Gag 蛋白 / アミノ酸挿入変異 / Gag 自壊

Research Abstract

We previously reported that amino acid (AA) insertions at certainpositions of Gag Capsid proteins (CA) caused significant CA degradation, and such AAinsert-containing HIV-1 variants had significantly compromised infectivity andreplication capacity. We attempted to identify small compounds capable of binding to CAbased on our previous data. We calculated binding scores of more than 8 million compoundswith the putative target cavity on CA using virtual docking simulation and evaluatingtheir anti-HIV-1 activity using the cell-based assay. We could find 29 compounds whichcan inhibit replication of HIV-1 by these methods.

Research Products

• [Journal Article] GRL-0519, A Novel OxatricyclicLigand-Containing Nonpeptidic HIV-1Protease Inhibitor (PI), PotentlySuppresses The Replication of a WideSpectrum of Multi-PI-Resistant HIV-1Variants In Vitro (2013)
  • Author(s): Masayuki Amano, Yasushi Tojo, PedroMiguel Salcedo-Gomez, Joseph RichardCampbell, Debananda Das, Manabu Aoki,Chun-Xiao Xu, Kalapala Venkateswara Rao,Arun K. Ghosh, and Hiroaki Mitsuya
  • Journal Title: Antimicrob AgentsChemother Volume: 57 Pages: 2036-2046
  • DOI: DOI:10.1128/AAC.02189-12
  • Peer Reviewed
• [Journal Article] Loss of the ProteaseDimerization Inhibition Activity ofTipranavir (TPV) and Its Associationwith the Acquisition of Resistance toTPV by HIV-1 (2012)
  • Author(s): Manabu Aoki, Matthew L. Danish, HiromiAoki-Ogata, Masayuki Amano, KazuhikoIde, Debananda Das, Yasuhiro Koh, andHiroaki Mitsuya
  • Journal Title: J. Virol Volume: 86 Pages: 13384-13396
  • DOI: DOI:10.1128/JVI.07234-11
  • Peer Reviewed
• [Journal Article] Substituent effects onP2-cyclopentyltetrahydrofuranylurethanes: Design, synthesis, and X-raystudies of potent HIV-1 proteaseinhibitors (2012)
  • Author(s): Arun K. Ghosh, Bruno D. Chapsal, MelindaSteffey, Johnson Agniswamy, Yuan-FangWang, Masayuki Amano, Irene T. Weber,Hiroaki Mitsuya
  • Journal Title: Bioorg Med Chem Lett Volume: 22(6) Pages: 2308-2311
  • DOI: DOI:10.1016/j.bmcl.2012.01.061
  • Peer Reviewed
• [Presentation] HIV-1capsid 蛋白(CA)の挿入変異がもたらすCA 自壊の分子機構の解明および CA 阻害活性を有する化合物の検索 (2012)
  • Author(s): 天野将之Pedro ,Miguel Salcedo-Gomez,Amber R Moore-Arthur, 満屋裕明
  • Organizer: 第26回日本エイズ学会学術集会
  • Place of Presentation: 慶応義塾大学日吉キャンパス
  • Year and Date: 2012-11-04
• [Presentation] Mechanism ofspontaneous degradation observed in theinsertion-containing HIV-1 Capsidproteins, and a new attempt to discoversmall compound which induce HIV-1Capsid protein degradation (2012)
  • Author(s): Masayuki Amano, Pedro Miguel SalcedoGomez, Amber R Moore-Arthur, andHiroaki Mitsuya
  • Organizer: 13thKmamoto AIDS Seminar-GCOE JointInternational Symposium
  • Place of Presentation: Aso-GranvirioHotel, Kumamoto, Japan
  • Year and Date: 2012-10-26
• [Presentation] Novel HIV-1 proteaseinhibitors with potent antiviralactivity and favorable blood brainbarrier penetration (2012)
  • Author(s): Pedro Miguel Salcedo-Gomez, MasayukiAmano, Arun K. Ghosh, and HiroakiMitsuya
  • Organizer: 13th Kmamoto AIDSSeminar-GCOE Joint InternationalSymposium
  • Place of Presentation: Aso-Granvirio Hotel,Kumamoto, Japan
  • Year and Date: 2012-10-26
• [Presentation] A Novel OxatricyclicLigand-Containing NonpeptidicProtease Inhibitor (PI) GRL-0519APotent Against Multi-PI-Resistant HIVIn Vitro (2012)
  • Author(s): Masayuki Amano, Y Tojo, M Aoki, S G.Pedro-Miguel, J R. Campbell, A K. Ghosh,H Mitsuya
  • Organizer: 25thInternational Conferenceon Antiviral Research (ICAR)
  • Place of Presentation: Royton Hotel, Sapporo,Japan
  • Year and Date: 2012-04-19