Open AccessAntiviral Stilbene 1,2-Diamines Prevent Initiation of Hepatitis C Virus RNA Replication at the Outset of Infection
Author(s) -
Pablo Gastaminza,
Suresh M. Pitram,
Marlène Dreux,
Larissa B. Krasnova,
Christina Whitten-Bauer,
Jiajia Dong,
Josan Chung,
Valery V. Fokin,
K. Barry Sharpless,
Francis V. Chisari
Publication year - 2011
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.02116-10
Subject(s) - ns5a , hepatitis c virus , biology , virology , rna , viral replication , clone (java method) , hepacivirus , viral entry , virus , hepatitis c , cell culture , gene , genetics
The recent development of a cell culture model of hepatitis C virus (HCV) infection based on the JFH-1 molecular clone has enabled discovery of new antiviral agents. Using a cell-based colorimetric screening assay to interrogate a 1,200-compound chemical library for anti-HCV activity, we identified a family of 1,2-diamines derived fromtrans -stilbene oxide that prevent HCV infection at nontoxic, low micromolar concentrations in cell culture. Structure-activity relationship analysis of ∼300 derivatives synthesized using click chemistry yielded compounds with greatly enhanced low nanomolar potency and a >1,000:1 therapeutic ratio. Using surrogate models of HCV infection, we showed that the compounds selectively block the initiation of replication of incoming HCV RNA but have no impact on viral entry, primary translation, or ongoing HCV RNA replication, nor do they suppress persistent HCV infection. Selection of an escape variant revealed that NS5A is directly or indirectly targeted by this compound. In summary, we have identified a family of HCV inhibitors that target a critical step in the establishment of HCV infection in which NS5A translatedde novo from an incoming genomic HCV RNA template is required to initiate the replication of this important human pathogen.