Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease.

ABSTRACT: Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds 4 and 5, were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PR_L76V). Compound 5 exhibited the best K _i value of 1.9 nM for PR_L76V, whereas the other three inhibitors had K _i values of 4.5-7.6 nM, 2-3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PR_L76V compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with Lys45 and Ile47 in the flap, and with Asp30 and Thr74 in the protein core, consisten

SUBMITTER: Wong-Sam A 

PROVIDER: S-EPMC6167001 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature