4区 · 医学
Article
作者: Badaroux, Eric ; Pierra, Claire ; Paparin, Jean-Laurent ; Griffe, Ludovic ; Onidi, Loredana ; Dukhan, David ; Griffon, Jean-François ; Leroy, Frédéric ; Bot, Stéphanie ; Dousson, Cyril B ; Milhau, Julien ; Surleraux, Dominique ; Da Costa, Daniel ; Rosinosky, Elodie ; Convard, Thierry ; Giulia Loi, Anna ; Mascia, Valeria ; Rahali, Rachid ; Sais, Efisio ; Amador, Agnès ; LaColla, Massimiliano ; Seifer, Maria ; Liuzzi, Michel ; Caillet, Catherine ; McCarville, Joe ; Standring, David
Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.