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. 2017 Jun 15;27(12):2689-2694.
doi: 10.1016/j.bmcl.2017.04.042. Epub 2017 Apr 20.

Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors with improved virology profile against gag polymorphisms

Jun Tang  1 , Stacey A Jones  2 , Jerry L Jeffrey  2 , Sonia R Miranda  2 , Cristin M Galardi  2 , David M Irlbeck  2 , Kevin W Brown  2 , Charlene B McDanal  2 , Brian A Johns  2
Affiliations

Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors with improved virology profile against gag polymorphisms

Jun Tang et al. Bioorg Med Chem Lett. .

Abstract

A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC50 values of 17nM, 23nM, 25nM, and 8nM for wild type, Q369H, V370A, and T371A respectively. When tested in a panel of 62 HIV-1 isolates covering a diversity of CA-SP1 genotypes including A, AE, B, C, and G using a PBMC based assay, GSK8999 was potent against 57 of 62 isolates demonstrating an improvement over the first generation maturation inhibitor BVM. The data disclosed here also demonstrated that the new α-keto amide GSK8999 has a mechanism of action consistent with inhibition of the proteolytic cleavage of CA-SP1.

Keywords: Betulin; Bevirimat; GSK8999; HIV-1; Maturation inhibitor.

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