Antiviral Stilbene 1,2-Diamines Prevent Initiation Of Hepatitis C Viral RNA Replication At The Outset of Infection

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J Virol. 2011 Mar 23. [Epub ahead of print]

Antiviral Stilbene 1,2-Diamines Prevent Initiation Of Hepatitis C Viral RNA

Replication At The Outset of Infection.

Gastaminza P, Pitram SM, Dreux M, Krasnova LB, Whitten-Bauer C, Dong J, Chung J,

Fokin VV, Sharpless KB, Chisari FV.

Department of Immunology and Microbial Science; Department of Chemistry, The

Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.

Abstract

The recent development of a cell culture model of 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

from trans-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 >1000:1 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 translated de novo from an incoming genomic HCV RNA

template is required to initiate the replication of this important human

pathogen.

PMID: 21430055 [PubMed - as supplied by publisher]