Development of highly active HIV fusion inhibitors

• Project/Area Number: 18K07158
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Murakami Tsutomu 国立感染症研究所, エイズ研究センター, 主任研究官 (50336385)
• Co-Investigator(Kenkyū-buntansha): 玉村 啓和 東京医科歯科大学, 生体材料工学研究所, 教授 (80217182)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: HIV / 膜融合 / 阻害剤 / 二量体化 / 阻害ペプチド / 二量体 / 低分子 / HIV-1 / I型膜融合 / 侵入阻害剤

Outline of Final Research Achievements

Membrane fusion is a valid target for inhibition of HIV-1 replication. A 34-mer fragment peptide (C34), which is contained in the HIV-1 envelope protein gp41, has significant anti-HIV activity. Previously, a dimeric derivative of C34 linked by a disulfide bridge at its C-terminus was found to have more potent anti-HIV activity than the C34 peptide monomer. To date, several peptidomimetic small inhibitors have been reported, but most have lower potency than peptide derivatives related to C34. In the present study we applied this dimerization concept to these peptidomimetic small inhibitors and designed several bivalent peptidomimetic HIV-1 fusion inhibitors. The importance of the length of linkers crosslinking two peptidomimetic compounds was demonstrated and several potent bivalent inhibitors containing tethered peptidomimetics were produced.

Academic Significance and Societal Importance of the Research Achievements

HIV膜融合に関する新たな知見を提供し、さらにより強力なHIVHIV膜融合阻害剤開発に向けた新戦略を提供できた。

Research Products

• [Journal Article] Bivalent HIV-1 fusion inhibitors based on peptidomimetics (2020)
  • Author(s): Kobayakawa T, Ebihara K, Tsuji K, Kawada T, Fujino M, Honda Y, Ohashi N, Murakami T, Tamamura H
  • Journal Title: Bioorg Med Chem. Volume: 28 Pages: 115812-115812
  • Peer Reviewed
• [Journal Article] Dimeric C34 derivatives linked through disulfide bridges as new HIV-1 fusion inhibitors. (2019)
  • Author(s): Kobayakawa, T., K. Ebihara, Y. Honda, M. Fujino, W. Nomura, N. Yamamoto, T. Murakami, and H. Tamamura
  • Journal Title: Chembiochem. Volume: なし Issue: 16 Pages: 2101-2108
  • DOI: 10.1002/cbic.201900187
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Matrix mutations that alter Gag membrane binding modulate mature core formation and post-entry events. (2019)
  • Author(s): Hikichi, Y., E. Takeda, M. Fujino, E. Nakayama, T. Matano, and T. Murakami
  • Journal Title: Virology Volume: 532 Pages: 97-107
  • DOI: 10.1016/j.virol.2019.04.013
  • Peer Reviewed / Open Access
• [Journal Article] Design, synthesis and biological evaluation of low molecular weight CXCR4 ligands (2019)
  • Author(s): 3.Sakyiamah MM., Kobayakawa T., Fujino M., KonnoM., Narumi T., Tanaka T., Nomura W., Yamamoto N., Murakami T., and Tamamura H.
  • Journal Title: Bioorg. Med. Chem Volume: 2 Issue: 6 Pages: 1130-1138
  • DOI: 10.1016/j.bmc.2019.02.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of human immunodeficiency virus type-1 Gag-TSG101 interaction inhibitors by high-throughput screening. (2018)
  • Author(s): 2.Siarot L., Chutiwitoonchai N., Sato H., Chang H., Sato H., Fujino M,. Murakami T., Aono T, Kodama E., Kuroda K., Takei M., Aida Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 503 Pages: 2970-2976
  • Peer Reviewed
• [Journal Article] Development of Anti-HIV Peptides Based on a Viral Capsid Protein (2017)
  • Author(s): Takaaki Mizuguchi, Nami Ohashi, Daichi Matsumoto, Chie Hashimoto, Wataru Nomura, Naoki Yamamoto, Tsutomu Murakami, Hirokazu Tamamura
  • Journal Title: Biopolymers: Peptide Science Volume: 印刷中 Issue: 1
  • DOI: 10.1002/bip.22920
  • Peer Reviewed
• [Presentation] 二量体化HIV-1膜融合阻害剤の作用機序 (2019)
  • Author(s): 村上 努、海老原健人、小早川拓也、藤野真之、児玉栄一、玉村啓和
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] 二量体化HIV-1膜融合阻害薬の作用機構 (2019)
  • Author(s): 村上 努、海老原健人、小早川拓也、藤野真之、児玉栄一、玉村啓和
  • Organizer: 第33回日本エイズ学会学術集会
• [Presentation] Biological and molecular characterization of a novel anti-HIV-1 compound created by in silico design and de novo organic synthesis. (2018)
  • Author(s): Murakami T, Fujino M, Yokoyama M, Kobayakawa T, Takeuchi H, Masuda T, Kotani O, Tamamura H, Sato H.
  • Organizer: Cold Spring Harbor Laboratory 43rd annual meeting on Retroviruses
  • Int'l Joint Research
• [Presentation] Development of new membrane fusion inhibitors against HIV-1 by dimerization strategy. (2018)
  • Author(s): Murakami T, Ebihara K, Fujino M, Honda Y, Kobayakawa T, Nomura W, Tamamura H. Development of new membrane fusion inhibitors against HIV-1 by dimerization strategy.
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Development of 2’-β Seleno nucleoside analogs as irreversible inhibitors for viral polymerases. (2018)
  • Author(s): Kimura Y, Niimi Y, Katakura H, Suzuki T, Murakami, T, Kodama E, Abe H.
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Development of 2’-β modified nucleosides for irreversible viral polymerases inhibitor. (2018)
  • Author(s): Niimi Y, Katakura H, Suzuki T, Takeda A, Murakami T, Kodama E, Abe H.
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] ウイルスポリメラーゼの不可逆的阻害を目指した新規2’-&βセレノ核酸アナログ. (2018)
  • Author(s): 村上 努、木村康明、新美結士、藤野真之、片倉秀雄、鈴木哲朗、児玉栄一、阿部 洋.
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] 二量体化に基づいた新規膜融合阻害剤の創出. (2018)
  • Author(s): 村上 努、海老原健人、藤野真之、本田柚子奈、小早川拓也、野村 渉、玉村啓和.
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] Characterization of Novel HIV-1 inhibitors targeting Gag-TSG101 interaction. (2018)
  • Author(s): L. Siarot、N. Chutiwitoonchai、佐藤洋隆、H. Chang、小谷 治、横山 勝、佐藤裕徳、藤野真之、村上 努、近藤恭光、本田香織、長田裕之、上田一樹、伊藤嘉浩、青野俊裕、児玉栄一、黒田和道、武井正美、間 陽子.
  • Organizer: 第32回日本エイズ学会学術集会・総会