A novel HIV-1 protease inhibitor, GRL-044, has potent activity against various HIV-1s with an extremely high genetic barrier to the emergence of HIV-1 drug resistance.

ABSTRACT: We designed, synthesized, and identified two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL- 037 and GRL-044, containing P2-tetrahydropyrano-tetrahydrofuran (Tp-THF), P1-benzene and P1-methoxybenzene, respectively, and P2'-isopropyl-aminobenzothiazole (Ip-Abt), based on the structure of the prototypic PI, darunavir (DRV). The 50% inhibitory concentrations (IC₅₀s) of GRL-037 and GRL-044 against wild-type HIV-1_NL4-3 were 0.042 and 0.0028-0.0033 nM with minimal cytotoxicity profiles compared to the IC₅₀ values of four most potent FDA-approved PIs, ranging from 2.6 to 70 nM. GRL-044 was also potent against HIV-2EHO (IC₅₀=0.0004 nM) and various PI-resistant HIV-1 variants (IC₅₀ ranging from 0.065 to 19 nM). In the selection assays w

SUBMITTER: Aoki M 

PROVIDER: S-EPMC7731189 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature