Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants.

ABSTRACT: A series of linear HCV NS3/4A protease inhibitors was designed by eliminating the P2-P4 macrocyclic linker in grazoprevir, which, in addition to conferring conformational flexibility, allowed structure-activity relationship (SAR) exploration of diverse quinoxalines at the P2 position. Biochemical and replicon data indicated preference for small hydrophobic groups at the 3-position of P2 quinoxaline for maintaining potency against resistant variants R155K, A156T, and D168A/V. The linear inhibitors, though generally less potent than the corresponding macrocyclic analogues, were relatively easier to synthesize and less susceptible to drug resistance. Three inhibitor cocrystal structures bound to wild-type NS3/4A protease revealed a conformation with subtle changes in the binding of P2 quinoxa

SUBMITTER: Rusere LN 

PROVIDER: S-EPMC6047049 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature