Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease.

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 I84Vthat provide resistance to the major clinical inhibitors. Compound 1had inhibition constants of 17-fold, 8-fold, 3-fold, and 3-fold, respectively, for PRD30N, PRI50V, PRV82A, and PRI84Vrelative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PRD30N, where inhibitor 1was approximately 3-fold less potent. The high resolution (1.11−1.60 Å) crystal structures of PR mutant complexes with inhibitor 1showed small changes relative to the wild type enzyme. PRD30Nand PRV82Ashowed compensating interactions with inhibitor 1relative to those of PR, while reduced hydrophobic contacts were observed with PRI50Vand PRI84V. Importantly, inhibitor 1complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV. [ABSTRACT FROM AUTHOR]