Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors with improved virology profile against gag polymorphisms.
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.
['Tang|Jun|J|', 'Jones|Stacey A|SA|', 'Jeffrey|Jerry L|JL|', 'Miranda|Sonia R|SR|', 'Galardi|Cristin M|CM|', 'Irlbeck|David M|DM|', 'Brown|Kevin W|KW|', 'McDanal|Charlene B|CB|', 'Johns|Brian A|BA|']
D000577:Amides D019380:Anti-HIV Agents D004305:Dose-Response Relationship, Drug D055808:Drug Discovery D015497:HIV-1 D008826:Microbial Sensitivity Tests D015394:Molecular Structure D011110:Polymorphism, Genetic D013329:Structure-Activity Relationship D014315:Triterpenes D054301:gag Gene Products, Human Immunodeficiency Virus
Maturation inhibitor HIV-1 GSK8999 Betulin Bevirimat