2013 Fiscal Year Final Research Report
Elucidation of the Emergence of HIV-1 Variants Resistant to HIV-1 Protease Dimerization Inhibitors (PDIs) and Development of Novel, Potent PDIs
| Project/Area Number |
23390265
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Infectious disease medicine
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| Research Institution | Kumamoto University |
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Principal Investigator |
MITSUYA Hiroaki 熊本大学, 大学院生命科学研究部, 教授 (20136724)
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| Research Collaborator |
GHOSH Arun K. 米国 Purdue 大学, 医学部, 教授
ARNORLD Eddy 米国 Rutgers 大学, 医学部, 教授
KOVARI Ladislau 米国 Wayne 州立大学, 医学部, 教授
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| Project Period (FY) |
2011-04-01 – 2014-03-31
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| Keywords | 感染症 / HIV / エイズ / HIV酵素二量体化阻害剤 / 創薬 |
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| Research Abstract |
In this study period, we designed, synthesized and identified two HIV-1 protease inhibitors (PIs), GRL-1388 and GRL-1398, which contain a tetrahydropyrano-tetrahydrofuran moiety and exert potent activity against multi-drug resistant variants including DRV-resistant HIV-1 strains. We also identified GRL-0519, which contains an oxatricyclic-tetrahydrofuran and exerts potent anti-HIV activity against a wide spectrum of drug-resistant HIV-1s and potent activity to block the dimerization of HIV-1 protease monomers. Additionally, we identified a novel PI, GRL-0739, which contains cyclohexane-bis-THF, and GRL-09510, which persistently exerts potent antiviral activity against various multi-drug resistant clinical isolates and laboratory-generated highly PI-resistant variants.
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[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, Antimicrob2013
Author(s)
Amano M, Tojo Y, Gomez PMS, Campbell JR, Das D, Aoki M, Xu CX, Rao KV, Ghosh AK, and Mitsuya H
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Journal Title
Agents Chemother
Volume: 57
Pages: 2036-2046
DOI
Peer Reviewed
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[Journal Article] Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands : Design, Synthesis, and Protein- Ligand X-ray Studies2013
Author(s)
Ghosh A, Partham GL, Martyr CD, Nyalapatla PR, Osswald HL, Agniswamy J, Wang YF, Amano M, Weber IT, Mitsuya H
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Journal Title
J. Med. Chem
Volume: 56
Pages: 6792-6802
DOI
Peer Reviewed
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[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 Structure2011
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
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Journal Title
Journal of Medicinal Chemistry
Volume: 54
Pages: 5890-5901
DOI
Peer Reviewed
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[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 variants2011
Author(s)
Kazuhiko Ide, Manabu Aoki, Masayuki Amano, Yasuhiro Koh, Ravikiran S. Yedidi, Debananda Das, Sofiya Leschenko, Bruno Chapsal, Arun K. Ghosh, Hiroaki Mitsuya
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Journal Title
Antimicrobial Agents and Chemotherapy
Volume: 55
Pages: 1717-1727
DOI
Peer Reviewed
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