Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease

摘要

The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, 150V, V82A, and 184V that provide resistance to the major clinical inhibitors. Compound I had inhibition constants of 17-fold, 8-fold, 3-fold, and 3-fold, respectively, for PRD30N, PR150V, PRv82A, and PR184v relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PRD30N, where inhibitor I was approximately 3-fold less potent. The high resolution (1.11-1.60 angstrom) crystal structures of PR mutant complexes with inhibitor I showed small changes relative to the wild type enzyme. PRD30N and PRv82A showed compensating interactions with inhibitor I relative to those of PR, while reduced hydrophobic contacts were observed with PR150v and PR184V. Importantly, inhibitor I complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV.