| Project/Area Number |
16K15520
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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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, 医学部附属病院, 特別招聘教授 (20136724)
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| Project Period (FY) |
2016-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2016: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
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| Keywords | HIV-1 / 薬剤耐性 / プロテアーゼ阻害剤 / 作用機序 / プロテアーゼ / 薬剤耐性機構 / 動的解析 / 表面プラズモン法 |
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| Outline of Final Research Achievements |
We previously identified multiple protease inhibitors (PIs) including GRL-015, -085, -097 and KU-241, which exert extremely potent activity against wild type HIV-1 (HIVWT) and a wide spectrum of drug-resistant HIV-1 variants such as drarunavir-resistance HIV-1 strains (HIVDRVRs). We also analyzed the relationships between the conformations of HIV protease (PR) and the activity of PIs using crystal structure examination and demonstrated that the interactions between PIs and the flap region of PR is important in blocking the replication of HIVDRVRs at IC50 values ranging 10-9 to 10-8 molar concentrations. In the present study, we evaluated the activity of novel PI, GRL-001, and solved the crystal structure of GRL-001- bound PR. The structural data showed that the PIs’ interactions with both-side flap regions are essential for the potent activity of GRL-001 against drug-resistant HIV-1 variants including HIVDRVRs.
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