A picomolar inhibitor of resistant strains of human immunodeficiency virusprotease identified by a combinatorial approach

In order to identify inhibitors of various drug-resistant forms of the huma n immunodeficiency virus protease (HIV PR), we have designed and synthesize d pseudopeptide libraries with a general structure Z-mimetic-Aa(1)-Aa(2)-NH 2. Five different chemistries for peptide bond replacement have been employ ed and the resulting five individual sublibraries tested with the HIV PR an d its drug-resistant mutants. Each mutant contains amino acid substitutions that have previously been shown to be associated with resistance to protea se inhibitors, including Ritonavir, Indinavir, and Saquinavir, We have mapp ed the subsite preferences of resistant HIV PR species with the aim of sele cting a pluripotent pharmaceutical lead. All of the enzyme species in this study manifest clear preference for an L-Glu residue in the P2' position. S light, but significant, differences in P3' subsite specificity among indivi dual resistant PR species have been documented. We have identified three co mpounds, combining the most favorable features of the inhibitor array, that exhibit low-nanomolar or picomolar K-i values for all three mutant PR spec ies tested. (C) 2000 Academic Press.