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

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Abstract
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 PRD30N, PRI50V, PRV82A, and PRI84V relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PRD30N, where inhibitor 1 was approximately 3-fold less potent. The high resolution (1.11−1.60 Å) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme. PRD30N and PRV82A showed compensating interactions with inhibitor 1 relative to those of PR, while reduced hydrophobic contacts were observed with PRI50V and PRI84V. Importantly, inhibitor 1 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.