GSK3640254 Is a Novel HIV-1 Maturation Inhibitor with an Optimized Virology Profile
Ira Dicker, Jerry L. Jeffrey, Tricia Protack, Zeyu Lin, Mark Cockett, Yan Chen, Sing-Yuen Sit, Martin Gartland, Nicholas A. Meanwell, Alicia Regueiro-Ren, Dieter Drexler, Joseph Cantone, Brian McAuliffe, Mark Krystal
Abstract
of 9 nM. Mechanistic studies established that bound GSK'254 dissociated on average 7.1-fold more slowly from wild-type Gag virus-like particles (VLPs) than a previous-generation MI. In resistance studies, the previously identified A364V Gag region mutation was selected under MI pressure in cell culture and during the phase IIa clinical study. As expected, GSK'254 inhibited cleavage of p25 in a range of polymorphic HIV-1 Gag VLPs. Virus-like particles containing the A364V mutation exhibited a p25 cleavage rate 9.3 times higher than wild-type particles, providing a possible mechanism for MI resistance. The findings demonstrate that GSK'254 potently inhibits a broad range of HIV-1 strains expressing Gag polymorphisms.