Antiviral Stilbene 1,2-Diamines Prevent Initiation of Hepatitis C Virus RNA Replication at the Outset of Infection

• DOI: 10.1128/jvi.02116-10
• Publication Date: 2011-03-24T02:04:54Z
• Authors: Pablo Gastaminza; Suresh M. Pitram; Marlene Dreux; Larissa B. Krasnova; Christina Whitten...; Jiajia Dong; Josan Chung; Valery V. Fokin; K. Barry Sharpless; Francis V. Chisari
• Keywords: NS5A; clone (Java method); Hepatitis C

The recent development of a cell culture model hepatitis C virus (HCV) infection based on the JFH-1 molecular clone has enabled discovery new antiviral agents. Using cell-based colorimetric screening assay to interrogate 1,200-compound chemical library for anti-HCV activity, we identified family 1,2-diamines derived from trans-stilbene oxide that prevent HCV at nontoxic, low micromolar concentrations in culture. Structure-activity relationship analysis ~ 300 derivatives synthesized using click chemistry yielded compounds with greatly enhanced nanomolar potency and > 1,000:1 therapeutic ratio. surrogate models infection, showed selectively block initiation replication incoming RNA but have no impact viral entry, primary translation, or ongoing replication, nor do they suppress persistent infection. Selection an escape variant revealed NS5A is directly indirectly targeted by this compound. In summary, inhibitors target critical step establishment which translated de novo genomic template required initiate important human pathogen.