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Antiviral Res. 2010 Jul;87(1):1-8. doi: 10.1016/j.antiviral.2010.03.013. Epub 2010 Apr 2.

A small molecule inhibits HCV replication and alters NS4B's subcellular distribution.

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  • 1Department of Medicine, Stanford University School of Medicine, CA 94305-5187, United States.

Abstract

Hepatitis C Virus (HCV) is a leading cause of liver disease and represents a significant public health challenge. Treatments for this disease are inadequate and improved antiviral therapies are necessary. Several such antivirals are in development, most of which target the well-characterized NS3 protease or the NS5B polymerase. In contrast, the nonstructural 4B (NS4B) protein, though essential for HCV RNA replication, has been the subject of few pharmacological studies. One of the functions ascribed to this protein is the ability to form intracellular membrane-associated foci (MAF), which are believed to be related to the sites of viral replication. Here, we report the identification of a small molecule that inhibits HCV replication and disrupts the organization of these MAF. Genetic analysis links the compound's mode of action to the NS4B gene product, and transient transfections of NS4B-GFP demonstrate that treatment with this compound can lead to the formation of novel elongated assemblies of NS4B. Furthermore, an in vitro dynamic light scattering assay provides evidence that the second amphipathic helix of NS4B may be the target of the drug. Our results demonstrate that this molecule represents a new potential class of HCV inhibitors and also provides us with a useful tool for studying the HCV life cycle.

2010 Elsevier B.V. All rights reserved.

PMID:
20363257
[PubMed - indexed for MEDLINE]
PMCID:
PMC3909674
Free PMC Article
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