Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection

Pablo Gastaminza, Suresh M. Pitram, Marlene Dreux, Larissa B. Krasnova, Christina Whitten-Bauer, Jiajia Dong, Josan Chung, Valery V. Fokin, K. Barry Sharpless, Francis V. Chisari

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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 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 >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 translated de novo from an incoming genomic HCV RNA template is required to initiate the replication of this important human pathogen.

Original languageEnglish
Pages (from-to)5513-5523
Number of pages11
JournalJournal of Virology
Volume85
Issue number11
DOIs
Publication statusPublished - Jun 2011
Externally publishedYes

Fingerprint

Stilbenes
diamines
Diamines
Hepatitis C virus
stilbenes
Virus Replication
Hepacivirus
Antiviral Agents
RNA
Virus Diseases
Infection
infection
cell culture
Cell Culture Techniques
RNA replication
Click Chemistry
Small Molecule Libraries
antiviral agents
chemical compounds
structure-activity relationships

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Gastaminza, P., Pitram, S. M., Dreux, M., Krasnova, L. B., Whitten-Bauer, C., Dong, J., ... Chisari, F. V. (2011). Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection. Journal of Virology, 85(11), 5513-5523. https://doi.org/10.1128/JVI.02116-10

Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection. / Gastaminza, Pablo; Pitram, Suresh M.; Dreux, Marlene; Krasnova, Larissa B.; Whitten-Bauer, Christina; Dong, Jiajia; Chung, Josan; Fokin, Valery V.; Sharpless, K. Barry; Chisari, Francis V.

In: Journal of Virology, Vol. 85, No. 11, 06.2011, p. 5513-5523.

Research output: Contribution to journalArticle

Gastaminza, P, Pitram, SM, Dreux, M, Krasnova, LB, Whitten-Bauer, C, Dong, J, Chung, J, Fokin, VV, Sharpless, KB & Chisari, FV 2011, 'Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection', Journal of Virology, vol. 85, no. 11, pp. 5513-5523. https://doi.org/10.1128/JVI.02116-10
Gastaminza, Pablo ; Pitram, Suresh M. ; Dreux, Marlene ; Krasnova, Larissa B. ; Whitten-Bauer, Christina ; Dong, Jiajia ; Chung, Josan ; Fokin, Valery V. ; Sharpless, K. Barry ; Chisari, Francis V. / Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection. In: Journal of Virology. 2011 ; Vol. 85, No. 11. pp. 5513-5523.
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