NDLI: Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Griffin, Stephen Stgelais, Corine Owsianka, Ania M. Patel, Arvind H. Rowlands, David Harris, Mark
Description	Country affiliation: United kingdom Author Affiliation: Griffin S ( Institute of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.)
Abstract	UNLABELLED: The hepatitis C virus (HCV) p7 protein plays a critical role during particle formation in cell culture and is required for virus replication in chimpanzees. The discovery that it displayed cation channel activity in vitro led to its classification within the 'viroporin' family of virus-coded ion channel proteins, which includes the influenza A virus (IAV) M2 protein. Like M2, p7 was proposed as a potential target for much needed new HCV therapies, and this was supported by our finding that the M2 inhibitor, amantadine, blocked its activity in vitro. Since then, further compounds have been shown to inhibit p7 function but the relationship between inhibitory effects in vitro and efficacy against infectious virus is controversial. Here, we have sought to validate multiple p7 inhibitor compounds using a parallel approach combining the HCV infectious culture system and a rapid throughput in vitro assay for p7 function. We identify a genotype-dependent and subtype-dependent sensitivity of HCV to p7 inhibitors, in which results in cell culture largely mirror the sensitivity of recombinant protein in vitro; thus building separate sensitivity profiles for different p7 sequences. Inhibition of virus entry also occurred, suggesting that p7 may be a virion component. Second site effects on both cellular and viral processes were identified for several compounds in addition to their efficacy against p7 in vitro. Nevertheless, for some compounds antiviral effects were specific to a block of ion channel function. CONCLUSION: These data validate p7 inhibitors as prototype therapies for chronic HCV disease. (HEPATOLOGY 2008;48:1779-1790.).
File Format	HTM / HTML
ISSN	02709139
Issue Number	6
Volume Number	48
e-ISSN	15273350
Journal	Hepatology
Language	English
Publisher	Wiley
Publisher Date	2008-12-01
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Discipline Hepatology Antiviral Agents Pharmacology Hepacivirus Drug Effects Genetics Viral Proteins Antagonists & Inhibitors 1-deoxynojirimycin Analogs & Derivatives Therapeutic Use Amantadine Amino Acid Sequence Carcinoma, Hepatocellular Pathology Virology Cell Line, Tumor Cell Survival Dose-response Relationship, Drug Genotype Hepatitis C Drug Therapy Humans Liver Neoplasms Molecular Sequence Data Rimantadine Analysis Virus Replication Journal Article Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Hepatology

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