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

• 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
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: HIV-1 / Gag 蛋白 / アミノ酸挿入変異 / Gag 自壊 / Capsid自壊 / HIV-1 Gag蛋白 / Capsid阻害剤 / Gag蛋白 / Gag蛋白自壊

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 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] 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] 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] Substituent effects on P2-cyclopentyltetrahydrofuranyl urethanes: Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors. (2012)
  • Author(s): Arun K. Ghosh, Bruno D. Chapsal, Melinda Steffey, Johnson Agniswamy, Yuan-Fang Wang, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters. Volume: 22 Pages: 2308-2311
  • Peer Reviewed
• [Journal Article] Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethane as P2-Ligands: Synthesis, Biological Evaluations, and Protein-Ligand X-ray Crystal Structure. (2011)
  • Author(s): Arun K. Ghosh, Bruno D. Chapsal, Garth L. Parham, Melinda Steffey, Johnson Agniswamy, Yuan-Fang Wang, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
  • Journal Title: Journal of Medicinal Chemistry. Volume: 54 Pages: 5890-5901
  • Peer Reviewed
• [Journal Article] Loss of Protease Dimerization Inhibition Activity of Durunavir Is Associated with the Acquisition of Resistance to Darunavir by HIV-1. (2011)
  • Author(s): Yasuhiro Koh, Manabu Aoki, Matthew L. Danish, Hiromi Aoki-Ogata, Masayuki Amano, Debananda Das, Robert W. Shafer, Arun K. Ghosh, Hiroaki Mitsuya.
  • Journal Title: Journal of Virology. Volume: 85 Pages: 10079-10089
  • Peer Reviewed
• [Journal Article] Design of Substituted Bis-tetrahydrofuran (Bis-THF)- Derived Potent HIV-1 Protease Inhibitors, Protein-Ligand X-ray Structure, and Convenient Syntheses of Bis-THF and Substituted Bis-THF Ligands. (2011)
  • Author(s): Arun K. Ghosh, Cuthbert D. Martyr, Melinda Steffey, Yuan-Fang Wang, Johnson Agniswamy, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
  • Journal Title: ACS Medicinal Chemistry Letters. Volume: 2 Pages: 298-302
  • Peer Reviewed
• [Journal Article] Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants. (2011)
  • Author(s): Kazuhiko Ide, Manabu Aoki, Masayuki Amano, Yasuhiro Koh, Ravikiran S. Yedidi, Debananda Das, Sofiya Leschenko, Bruno Chapsal, Arun K. Ghosh, Hiroaki Mitsuya.
  • Journal Title: Antimicrobial Agents and Chemotherapy. Volume: 55 Pages: 1717-1727
  • Peer Reviewed
• [Journal Article] Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol -Derived High Affinity P2 Ligands: Structure-Activity Studies and Biological Evaluation. (2011)
  • Author(s): Arun K. Ghosh, Bruno D. Chapsal, Abigail Baldridge, Melinda P. Steffey, D. Eric Walters, Yasuhiro Koh, Masayuki Amano, Hiroaki Mitsuya.
  • Journal Title: Journal of Medicinal Chemistry. Volume: 54 Pages: 622-634
  • Peer Reviewed
• [Journal Article] 多剤耐性株に高い抗ウイルス活性を発揮する新規抗HIVプロテアーゼ阻害剤の同定・開発とGag capsid蛋白挿入変異とCA自壊の分子機構の研究(第11回ECC山口メモリアルエイズ研究奨励賞受賞研究) (2011)
  • Author(s): 天野将之
  • Journal Title: 日本エイズ学会誌 Volume: 13 Pages: 70-75
• [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
• [Presentation] A Novel Oxatricyclic-Ligand- Containing Nonpeptidic Protease Inhibitor (PI) GRL-0519A Potent Against Multi-PI-Resistant HIV In Vitro. (2012)
  • Author(s): Masayuki Amano, Hiroaki Mitsuya, et al.
  • Organizer: 25th International Conference on Antiviral Research (ICAR).
  • Place of Presentation: 北海道 ロイトン札幌
• [Presentation] HIV-1 capsid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、満屋裕明, et al.
  • Organizer: 第26回日本エイズ学会学術集会
  • Place of Presentation: 神奈川 慶應義塾大学日吉キャンパス
• [Presentation] Mechanism of spontaneous degradation observed in the insertion-containing HIV-1 Capsid proteins, and a new attempt to discover small compound which induce HIV-1 Capsid protein degradation (2012)
  • Author(s): Masayuki Amano, Hiroaki Mitsuya, et al.
  • Organizer: 13th Kmamoto AIDS Seminar-GCOE Joint International Symposium.
  • Place of Presentation: 熊本 阿蘇リゾート グランヴィリオホテル
• [Presentation] Novel HIV-1 protease inhibitors with potent antiviral activity and favorable blood brain barrier penetration. (2012)
  • Author(s): Pedro Miguel Salcedo-Gomez, Masayuki Amano, Hiroaki Mitsuya, et al.
  • Organizer: 13th Kmamoto AIDS Seminar-GCOE Joint International Symposium.
  • Place of Presentation: 熊本 阿蘇リゾート グランヴィリオホテル
• [Presentation] A Novel Oxatricyclic-Ligand-Containing Nonpeptidic Protease Inhibitor (PI) GRL-0519A Potent Against Multi-PI-Resistant HIV In Vitro. (2012)
  • Author(s): Masayuki Amano
  • Organizer: 25th International Conference on Antiviral Research (ICAR)
  • Place of Presentation: 札幌、ロイトン札幌
• [Presentation] HIV-1 capsid蛋白 (CA) の挿入変異がもたらすCA自壊の分子機構の解明 (2011)
  • Author(s): 天野将之
  • Organizer: 第25回日本エイズ学会学術集会
  • Place of Presentation: 東京、ハイアットリージェンシー東京
• [Presentation] Oxatricyclic (tris-tetrahydrofuranylurethane: tris-THF) 構造を有する新規のHIVプロテアーゼ阻害剤 (PI)，GRL-0519の抗ウイルス活性の検討 (2011)
  • Author(s): 天野将之、満屋裕明
  • Organizer: 第21回抗ウイルス療法研究会
  • Place of Presentation: 金沢、金沢市文化センター