Inhibition of hepatitis C virus NS5B polymerase by S-trityl-l-cysteine derivatives

Structure-based studies led to the identification of a constrained derivative of S-trityl-l-cysteine (STLC) scaffold as a candidate inhibitor of hepatitis C virus (HCV) NS5B polymerase. A panel of STLC derivatives were synthesized and investigated for their activity against HCV NS5B. Three STLC derivatives, 9, F-3070, and F-3065, were identified as modest HCV NS5B inhibitors with IC50 values between 22.3 and 39.7 μM. F-3070 and F-3065 displayed potent inhibition of intracellular NS5B activity in the BHK-NS5B-FRLuc reporter and also inhibited HCV RNA replication in the Huh7/Rep-Feo1b reporter system. Binding mode investigations suggested that the STLC scaffold can be used to develop new NS5B inhibitors by further chemical modification at one of the trityl phenyl group.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► HCV NS5B inhibitors were designed employing structure-based protocol. ► Some of the designed compounds were obtained via a facile synthetic approach. ► Enzyme and cell based assays proved STLC as leads against HCV NS5B.