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, I50V, V82A, and I84V that provide resistance to the major clinical inhibitors. Compound 1 had inhibition constants of 17-fold, 8-fold, 3-fold, and 3-fold, respectively, for PR_(D30N) PR_(I50V), PR_(V82A and PR_(I84V) relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PR_(D30N), where inhibitor 1 was approximately 3-fold less potent. The high resolution (1.11-1.60 A) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme.