Development of novel anti-HIV-1 agents which induce significant degradation of HIV-1 capsid protein.
Project/Area Number |
15K09574
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Infectious disease medicine
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Research Institution | Kumamoto University |
Principal Investigator |
Amano Masayuki 熊本大学, 医学部附属病院, 特任助教 (30575080)
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Project Period (FY) |
2015-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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Keywords | HIV-1 / capsid蛋白 / 蛋白自己崩壊 / 薬剤開発 / 新規抗HIV-1剤開発 / HIV-1 キャプシド蛋白 / キャプシド構造蛋白 / 蛋白崩壊 / 創薬 / HIV-1 Capsid 蛋白 (CA) / 新規薬剤開発 / HIV-1構造蛋白阻害 / CA 自己崩壊 / 新規 HIV CA 阻害剤 |
Outline of Final Research Achievements |
The aim of our research is to develop the novel anti-HIV-1 (HIV) agents which bind to HIV capsid structural protein (CA) and induce significant CA degradation. We carried out in silico docking simulation of each of 8 million compounds data with a target cavity we identified on the surface of CA N-terminal domain (NTD), then evaluated in vitro anti-HIV activity of compounds with good binding score. We have newly identified ~50 compounds which have anti-HIV activity, among them, 3 compounds significantly induced CA degradation. Such compounds induce degradation both of newly generated CA in the infected cells and conical core-formed CAs within mature HIV virion by penetrating through viral membrane. We also identified that the CA-degradation-inducing compound bind to the NTD of CA. We have newly synthesized structurally-related compounds with CA-degradation-inducing compounds for the optimization, and applied for domestic/international patents regarding CA-degradation-inducing compounds.
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Academic Significance and Societal Importance of the Research Achievements |
既存の多剤併用化学療法はHIVの酵素群を標的としているが、対して本研究の標的CAは、HIV内でウイルス遺伝子を包む円錐状殻を構成する蛋白である。本研究はHIVの“本丸”を攻める戦略であり、既存薬とは一線を画す。 HIV逆転写酵素に起因する高い突然変異発生率・HIV酵素群の持つ変異への高許容性より薬剤耐性株出現が惹起される。対してCAはよく保存された領域であり遺伝子変異出現への許容性が低い事が示唆され、CA阻害剤にHIVが薬剤耐性を獲得する事は困難と推測される。CA自壊の誘導及びそれに起因するHIV感染・増殖阻害といった、前例の無い作用機序の薬剤開発は、HIV感染症治療の新たな選択肢に成り得る。
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Report
(5 results)
Research Products
(35 results)
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[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.
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Journal Title
ACS Medicinal Chemistry Letters.
Volume: 9(12)
Issue: 12
Pages: 1211-1216
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Journal of Medicinal Chemistry.
Volume: 61(10)
Issue: 10
Pages: 4561-4577
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[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.
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Journal Title
ChemistrySelect.
Volume: 3(11)
Issue: 11
Pages: 3313-3317
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Design, synthesis, biological evaluation, and X-ray studies of HIV-1 protease inhibitors with modified P2'-ligands of Darunavir.2017
Author(s)
Arun K Ghosh, W. Sean Fyvie, Margherita Brindisi, Melinda Steffey, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
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Journal Title
ChemMedChem
Volume: 12
Issue: 23
Pages: 1942-1952
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1′-P2′ ligands2017
Author(s)
Arun K. Ghosh, W. Sean Fyvie, Margherita Brindisi, Melinda Steffey, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya
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Journal Title
Bioorganic & Medicinal Chemistry Letters
Volume: 27
Issue: 21
Pages: 4925-4931
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex.2017
Author(s)
Arun K. Ghosh , Margherita Brindisi, Prasanth R. Nyalapatla, Jun Takayama, Jean-Rene Ella-Menye, Sofiya Yashchuk, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya
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Journal Title
Bioorganic & Medicinal Chemistry
Volume: 25
Issue: 19
Pages: 5114-5127
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] A Modified P1 Moiety Enhances in vitro Antiviral Activity against Various Multi-Drug-Resistant HIV-1 Variants and in vitro CNS Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413.2016
Author(s)
2.Masayuki Amano, Pedro Salcedo-Gómez, Rui Zhao, Ravikiran Yedidi, Debananda Das, Haydar Bulut, Nicole Delino, Sheri Reddy, Arun Ghosh, and Hiroaki Mitsuya
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Journal Title
Antimicrob Agents Chemother.
Volume: 60
Issue: 12
Pages: 7046-7059
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Diastereoselective Synthesis of 6" (Z)- and 6" (E) Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers2016
Author(s)
Hiroki Kumamoto, Misato Fukano, Tomohiko Nakano, Keito Iwagami, Chiaki Takeyama, Satoru Kohgo, Shuhei Imoto, Masayuki Amano, Nobuyo Kuwata-Higashi, Manabu Aoki, Hiroshi Abe, Hiroaki Mitsuya, Kiyoshi Fukuhara, Kazuhiro Haraguchi
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Journal Title
Journal of Organic Chemistry
Volume: 81
Issue: 7
Pages: 2827-2836
DOI
Related Report
Peer Reviewed
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[Journal Article] Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation.2015
Author(s)
Arun K. Ghosh, Sofiya Yashchuk, Akira Mizuno, Nilanjana Chakraborty, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Pedro Miguel Salcedo Gomez, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
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Journal Title
ChemMedChem
Volume: 10
Issue: 1
Pages: 107-115
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Design, Synthesis and Evaluation of Anti-HBV Activity of Hybrid Molecules of Entecavir and Adefovir: Exomethylene Acycloguanine Nucleosides and its Monophosphate Derivatives.2015
Author(s)
Shuhei Imoto, Satoru Kohgo, Ryoh Tokuda, Hiroki Kumamoto, Manabu Aoki, Masayuki Amano, Nobuyo Kuwata-Higashi, Hiroaki Mitsuya, Kazuhiro Haraguchi.
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Journal Title
Nucleosides, nucleotides & Nucleic Acids
Volume: 34
Issue: 8
Pages: 590-602
DOI
Related Report
Peer Reviewed
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[Journal Article] 4’-Modified Nucleoside Analogs: Potent Inhibitors Active against Entecavir-resistant HBV.2015
Author(s)
Yuki Takamatsu, Yasuhito Tanaka, Satoru Kohgo, Shuko Murakami, Kamlendra Singh, Debananda Das, David J. Venzon, Masayuki Amano, Nobuyo Kuwata, Manabu Aoki, Nicole S. Delino, Sanae Hayashi, Satoru Takahashi, Yoshikazu Sukenaga, Kazuhiro Haraguchi, Stefan G. Sarafianos, Kenji Maeda, Hiroaki Mitsuya.
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Journal Title
Hepatology
Volume: 62
Issue: 4
Pages: 1024-1036
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands.2015
Author(s)
Arun K. Ghosh, Jun Takayama, Luke A. Kassekert, Jean-Rene Ella-Menye, Sofiya Yashchuk, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
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Journal Title
Bioorg Med Chem Lett.
Volume: 25
Issue: 21
Pages: 4903-4909
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands.2015
Author(s)
Arun K. Ghosh, Cuthbert D. Martyr, Luke A. Kassekert, Prasanth R. Nyalapatla, Melinda Steffey, Johnson Agniswamy, Yuan-Fang Wang, Irene T. Weber, Masayuki Amano, Hiroaki Mitsuya.
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Journal Title
Org. Biomol. Chem.
Volume: 13
Issue: 48
Pages: 11607-11621
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Immunomodulatory drugs act as inhibitors of DNA methyltransferases and induce PU.1 up-regulation in myeloma cells.2015
Author(s)
Endo S, Amano M, Nishimura N, Ueno N, Ueno S, Yuki H, Fujiwara S, Wada N, Hirata S, Hata H, Mitsuya H, Okuno Y.
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Journal Title
Biochem Biophys Res Commun.
Volume: 469
Issue: 2
Pages: 236-242
DOI
Related Report
Peer Reviewed
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