An HIV Candidate from a Natural Product

GSK3640254, one of January 2022's Molecules of the Month, is an HIV maturation inhibitor and Ph. IIb clinical candidate (60-180 mg PO QD) with activity against a range of HIV strains with Gag polymorphisms.

The first HIV maturation inhibitor to read out clinically was bevirimat (Myriad Genetics), derived from a natural product first isolated from a Chinese herb. Maturation inhibitors like GSK3640254 work by binding to the cleavage site of the Gag protein, preventing release of p24 and formation of proper HIV capsids.
 
Unfortunately, the initial drug was not efficacious enough due to polymorphisms in HIV Gag protein leading to resistance (response in only ~50% of patients). GSK had another clinical candidate, GSK3532795 in clinical trials, but this was discontinued due to GI tolerability issues in a Ph. IIb study when combined with emtricitabine and tenofovir.
 
GSK3640254 is believed to be safer and also has deeper target coverage at trough exposure (150 nM) on a broader range of polymorphisms, hopefully leading to more durable efficacy.
 
The molecule is an interesting example of a clinical candidate with three olefins and a primary alkyl fluoride. The primary differences between GSK3532795 and GSK3640254 structurally are on the left-hand portion, with a benzoic acid replaced by the semi-saturated motif present in ‘254.