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Biochem Biophys Res Commun. 2013 Nov 1;440(4):515-20. doi: 10.1016/j.bbrc.2013.09.100. Epub 2013 Oct 5.

Specific inhibition of hepatitis C virus entry into host hepatocytes by fungi-derived sulochrin and its derivatives.

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  • 1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan.

Abstract

Hepatitis C virus (HCV) is a major causative agent of hepatocellular carcinoma. Although various classes of anti-HCV agents have been under clinical development, most of these agents target RNA replication in the HCV life cycle. To achieve a more effective multidrug treatment, the development of new, less expensive anti-HCV agents that target a different step in the HCV life cycle is needed. We prepared an in-house natural product library consisting of compounds derived from fungal strains isolated from seaweeds, mosses, and other plants. A cell-based functional screening of the library identified sulochrin as a compound that decreased HCV infectivity in a multi-round HCV infection assay. Sulochrin inhibited HCV infection in a dose-dependent manner without any apparent cytotoxicity up to 50 μM. HCV pseudoparticle and trans-complemented particle assays suggested that this compound inhibited the entry step in the HCV life cycle. Sulochrin showed anti-HCV activities to multiple HCV genotypes 1a, 1b, and 2a. Co-treatment of sulochrin with interferon or a protease inhibitor telaprevir synergistically augmented their anti-HCV effects. Derivative analysis revealed anti-HCV compounds with higher potencies (IC50<5 μM). This is the first report showing an antiviral activity of methoxybenzoate derivatives. Thus, sulochrin derivatives are anti-HCV lead compounds with a new mode of action.

KEYWORDS:

Compound; CsA; Entry; HBV envelope protein; HBs; HCV; HCV derived from cell culture; HCV pseudoparticle; HCV trans-complemented particle; HCVcc; HCVpp; HCVtcp; IFN; MOI; Natural product; Screening; Sulochrin; VSV; cyclosporin A; hepatitis C virus; interferon; multiplicity of infection; vesicular stomatitis virus

PMID:
24099774
DOI:
10.1016/j.bbrc.2013.09.100
[PubMed - indexed for MEDLINE]
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