Investigation of novel mechanism(s) regarding HIV-1 capsid protein degradation and uncoating

• Project/Area Number: 18K08435
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Kumamoto University
• Principal Investigator: Amano Masayuki 熊本大学, 病院, 特別研究員 (30575080)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HIV-1 / キャプシド蛋白 / 蛋白自己崩壊 / 脱殻 / HIV-1 キャプシド蛋白 / キャプシド構造蛋白

Outline of Final Research Achievements

Capsid protein (CA), which is an essential structural protein for HIV-1 and forms a shell that encloses a viral RNA, maintains the shell structure with a certain strength in order to protect the viral RNA in the virion. On the other hand, in order to collapse CA shell smoothly and transport viral RNA to the nuclease (so-called “uncoating”) while new infection, it is also necessary for CA to have a certain degree of "instability". In this project, we newly discovered that 9 amino acids sequence (9AA) of CA C-terminal domain (CTD) is important factor for CA degradation, and that infectivity and replicative capacity are significantly impaired in HIV-1 variants containing CTD-9AA deleted CA.

Academic Significance and Societal Importance of the Research Achievements

本研究ではHIV-1の必須構造蛋白であるキャプシド（CA）で認めるCA自己崩壊（自壊）の責任領域やその機序を検討し、更にHIV-1の脱殻・複製に対しCA自壊が及ぼす影響について評価するものであり、不明な点が多いHIV-1の細胞感染初期、特に脱殻時におけるCAの動態に関し、新たなコンセンサスの確立に貢献し得る可能性がある。更に得られた知見はCAを有する他のウイルスに関しても応用可能と考えられる。

Research Products

• [Journal Article] A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor (2020)
  • Author(s): Nakamura Tomofumi、Nakamura Teruya、Amano Masayuki、Miyakawa Toshikazu、Yamagata Yuriko、Matsuoka Masao、Nakata Hirotomo
  • Journal Title: Journal of Virology Volume: 94 Issue: 19 Pages: 1-20
  • DOI: 10.1128/jvi.00486-20
  • Peer Reviewed
• [Journal Article] Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies (2020)
  • Author(s): Ghosh Arun K.、Kovela Satish、Osswald Heather L.、Amano Masayuki、Aoki Manabu、Agniswamy Johnson、Wang Yuan-Fang、Weber Irene T.、Mitsuya Hiroaki
  • Journal Title: Journal of Medicinal Chemistry Volume: 63 Issue: 9 Pages: 4867-4879
  • DOI: 10.1021/acs.jmedchem.0c00202
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Amino-acid inserts of HIV-1 capsid (CA) induce CA degradation and abrogate viral infectivity: Insights for the dynamics and mechanisms of HIV-1 CA decomposition. (2019)
  • Author(s): Masayuki Amano, Haydar Bulut, Sadahiro Tamiya, Tomofumi Nakamura, Yasuhiro Koh, Hiroaki Mitsuya.
  • Journal Title: Scientific Reports. Volume: 9 Issue: 1 Pages: 9806-9806
  • DOI: 10.1038/s41598-019-46082-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications (2019)
  • Author(s): Masayuki Amano, Pedro Miguel Salcedo-Gomez, Ravikiran S. Yedidi, Rui Zhao, Hironori Hayashi, Kazuya Hasegawa, Tomofumi Nakamura, Cuthbert D. Martyr, Arun K. Ghosh, Hiroaki Mitsuya.
  • Journal Title: Antimicrobial Agents and Chemotherapy. Volume: 63 Issue: 7 Pages: 1-1
  • DOI: 10.1128/aac.00466-19
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 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 (2019)
  • Author(s): 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.
  • Journal Title: Antimicrobial Agents and Chemotherapy. Volume: 63 Issue: 8 Pages: 1-1
  • DOI: 10.1128/aac.00372-19
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis, Anti-HBV, and Anti-HIV Activities of 3’-Halogenated Bis(hydroxymethyl)-cyclopentenyladenines. (2018)
  • Author(s): 1.Hiroki Kumamoto, Shuhei Imoto, Masayuki Amano, Nobuyo Kuwata-Higashi, Masanori Baba, Hiroaki Mitsuya, Yuki Odanaka, Satoko Shimbara Matsubayashi, Hiromichi Tanaka, Kazuhiro Haraguchi.
  • Journal Title: ACS Medicinal Chemistry Letters. Volume: 9(12) Issue: 12 Pages: 1211-1216
  • DOI: 10.1021/acsmedchemlett.8b00374
  • Peer Reviewed
• [Journal Article] Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis. (2018)
  • Author(s): 2.Arun K. Ghosh, Prasanth R. Nyalapatla, Satish Kovela, Kalapala Venkateswara Rao, Margherita Brindisi, Heather L. Osswald, Masayuki Amano, Manabu Aoki, Johnson Agniswamy, Yuan-Fang Wang, Irene T. Weber, Hiroaki Mitsuya.
  • Journal Title: Journal of Medicinal Chemistry. Volume: 61(10) Issue: 10 Pages: 4561-4577
  • DOI: 10.1021/acs.jmedchem.8b00298
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis of 4’‐Substituted Purine 2’‐Deoxynucleosides and Their Activity against Human Immunodeficiency Virus Type 1 and Hepatitis B Virus. (2018)
  • Author(s): 3.Satoru Kohgo, Shuhei Imoto, Ryoh Tokuda, Yuki Takamatsu, Nobuyo Higashi-Kuwata, Manabu Aoki, Masayuki Amano, Hisao Kansui, Kengo Onitsuka, Kenji Maeda, Hiroaki Mitsuya.
  • Journal Title: ChemistrySelect. Volume: 3(11) Issue: 11 Pages: 3313-3317
  • DOI: 10.1002/slct.201800527
  • Peer Reviewed / Open Access
• [Presentation] 感染効率を上昇させるHIV-1ヌクレオカプシド内に認められた薬剤耐性変異 (2020)
  • Author(s): 中村朋文、天野将之、Travis Chia、松岡雅雄、中田浩智
  • Organizer: 第34回日本エイズ学会学術集会・総会
• [Presentation] Determining the Mechanism of a Possible HIV-1 Capsid Inhibitor: ACAi-028 (2020)
  • Author(s): Travis Chia、Masayuki Amano、Tomofumi Nakamura、Hirotomo Nakata、Masao Matsuoka.
  • Organizer: 第34回日本エイズ学会学術集会・総会
• [Presentation] 高い中枢神経系移行性と強力な抗HIV活性を有する新規HIV関連神経認知障害（HAND）予防/治療薬の開発 (2019)
  • Author(s): 天野 将之、Pedro Miguel Salcedo-Gomez、Ravikiran S. Yedidi、趙 睿、林 宏典、長谷川 和也、Cuthbert D. Martyr、Arun K. Ghosh、満屋 裕明
  • Organizer: 第29回抗ウイルス療法学会学術集会・総会
• [Presentation] HIV-1 capsid (CA) 構造蛋白に作用し、その過剰安定化を誘導する事でHIV-1増殖阻害活性を発揮する化合物群の同定 (2019)
  • Author(s): 天野 将之、中村 朋文、Pedro Miguel Salcedo-Gomez、趙 睿、中田 浩智、宮川 寿一、Travis Chia Ren Teen、松岡 雅雄、満屋 裕明
  • Organizer: 第33回日本エイズ学会学術集会・総会
• [Presentation] HIV-1の必須構造蛋白であるキャプシドに対する新規阻害剤の開発 (2019)
  • Author(s): 天野 将之、中村 朋文、杉浦 正晴、高宗 暢暁、松岡 雅雄、満屋 裕明
  • Organizer: 第47回構造活性相関シンポジウム
• [Presentation] HIV-1 capsid (CA) 構造蛋白において、C末端アミノ酸が寄与するCA蛋白不安定性に関するウイルス学的考察 (2018)
  • Author(s): 天野 将之、趙 睿、中村 朋文、中田 浩智、宮川 寿一、松岡 雅雄、満屋 裕明
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] Identification and Development of Novel Anti-HIV-1 Compounds which Induce Hyper-stabilization of HIV-1’s Capsid Structural Protein (CA)/ HIV-1 キャプシド構造蛋白の過剰安定化を促進させる事でウイルス増殖を抑制する、新規抗HIV-1化合物の開発 (2018)
  • Author(s): 天野 将之
  • Organizer: BioJapan 2018
  • Int'l Joint Research
• [Presentation] HIV-1 capsid構造蛋白（CA）の安定性を変化させる事で抗ウイルス作用を発揮する、CA自己崩壊誘導化合物（CA decomposers）及びCA安定化過剰促進化合物（CA hyper-stabilizers）の開発 (2018)
  • Author(s): 53.天野 将之、中村 朋文、Salcedo Gomez Pedro Miguel、趙 睿、中田 浩智、宮川 寿一、松岡 雅雄、満屋 裕明
  • Organizer: 第20回白馬シンポジウム
• [Patent(Industrial Property Rights)] 抗HIV医薬組成物 (2019)
  • Inventor(s): 天野 将之、中村 朋文
  • Industrial Property Rights Holder: 天野 将之、中村 朋文
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-102088
  • Filing Date: 2019