| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2014: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
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| Outline of Final Research Achievements |
We identified newly generated novel protease inhibitors (GRL-058, -059, -077, -078, -079, -010 and -014), which were designed based on the structural, pharmaceutical and anti-HIV activity features of GRL-085 and KU-241 (Aoki & Mitsuya, J Virol. 90, 2180-2194, 2016). We also determined the anti-HIV activity and crystal structures of these derivatives. These compounds exerted potent activity with IC50 values of 10-11 to 10-8 molar concentrations against wild type HIV-1 (HIVWT) and darunavir (DRV)-resistant HIV-1 variants (HIVDRVRs). We also identified the chemical moieties, which confer the potent activity against HIVDRVRs on some compounds through forming strong halogen and hydrogen bonds with amino acids located at the flap region of protese. Additionally, we demonstrated that such compounds had higher genetic barrier than DRV using in vitro selection assay for inducing drug resistant HIV-1 strains.
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