DESIGN, SYNTHESIS, AND RESISTANCE PATTERNS OF MP-134 AND MP-167, 2 NOVEL INHIBITORS OF HIV TYPE-1 PROTEASE

Inhibitors of HIV-1 protease represent a new class of antiretroviral c ompounds, Here, we report the design and synthesis of two novel C2 sym metry-based inhibitors, MP-134 and MP-167, specifically targeted again st HIV-1 variants with reduced sensitivity to another related protease inhibitor, A-77003. In addition, we describe the in vitro selection o f viral variants with reduced sensitivity to these two protease inhibi tors. An isoleucine-to-valine substitution at residue 84 (I84V) of the HIV-1 protease confers resistance to MP-134, whereas a glycine-to-val ine substitution at residue 48 (G48V) confers resistance to MP-167, Te sting other protease inhibitors against these variants has revealed sp ecific overlapping patterns of resistance among these agents, These fi ndings have important implications in the design of combination regime ns using multiple protease inhibitors and underscore the need to devel op non-cross-resistant compounds to be used toward this goal.