| Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection. | |
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MedLine Citation:
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PMID: 21430055 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-03-23 |
Journal Detail:
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Title: Journal of virology Volume: 85 ISSN: 1098-5514 ISO Abbreviation: J. Virol. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-05-09 Completed Date: 2011-07-13 Revised Date: 2013-05-24 |
Medline Journal Info:
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Nlm Unique ID: 0113724 Medline TA: J Virol Country: United States |
Other Details:
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Languages: eng Pagination: 5513-23 Citation Subset: IM |
Affiliation:
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Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 9203, USA. pgastaminza@cnb.csic.es |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antiviral Agents
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chemistry,
isolation & purification,
pharmacology*,
toxicity Cell Line Cell Survival / drug effects Diamines / chemistry, isolation & purification, pharmacology*, toxicity Drug Evaluation, Preclinical / methods Drug Resistance, Viral Hepacivirus / drug effects* Hepatocytes / drug effects, virology Humans Microbial Sensitivity Tests RNA, Viral / metabolism Stilbenes / chemistry, isolation & purification, pharmacology*, toxicity Structure-Activity Relationship Viral Nonstructural Proteins / genetics, metabolism Virus Replication / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM087620/GM/NIGMS NIH HHS; R01 GM087620-04/GM/NIGMS NIH HHS; R01-AI079043/AI/NIAID NIH HHS; R01-CA108304/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antiviral Agents; 0/Diamines; 0/NS-5 protein, hepatitis C virus; 0/RNA, Viral; 0/Stilbenes; 0/Viral Nonstructural Proteins |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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