Document Detail


Antiviral stilbene 1,2-diamines prevent initiation of hepatitis C virus RNA replication at the outset of infection.
MedLine Citation:
PMID:  21430055     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Related Documents :
21291655 - Practical techniques to enhance the safety of health care workers in office-based surgery.
21466895 - Roles of tipe2 in hepatitis b virus-induced hepatic inflammation in humans and mice.
12853875 - Travel, tourism, and hiv risk among older adults.
11304705 - Assessing basic hiv transmission risks and the contextual factors associated with hiv r...
2537545 - Delineation of false-positive hiv antibody response in patients with renal failure and ...
17034705 - Accuracy and cost-benefit of pooled versus singleton screening blood donations for anti...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-23
Journal Detail:
Title:  Journal of virology     Volume:  85     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-09     Completed Date:  2011-07-13     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5513-23     Citation Subset:  IM    
Affiliation:
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 9203, USA. pgastaminza@cnb.csic.es
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Antiviral Agents / 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:
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:
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


Previous Document:  Activation of the alphavirus spike protein is suppressed by bound E3.
Next Document:  Sequential immunization with a subtype B HIV-1 envelope quasispecies partially mimics the in vivo de...