The molecular mechanism of HIV-1's drug resistance against protease inhibitors including darunavir and the development of novel resistance-repelling protease inhibitors

2016 Fiscal Year Final Research Report

• Project/Area Number: 26293239
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: MITSUYA Hiroaki 熊本大学, 医学部附属病院, 特別招聘教授 (20136724)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: HIV-1 / 新薬開発 / プロテアーゼ阻害剤 / 構造解析

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.

Free Research Field

血液内科学・免疫学・ウイルス学・分子生物学