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

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.

• Authors: Syo Nakajima, Koichi Watashi, Shinji Kamisuki, Senko Tsukuda, Kenji Takemoto, Mami Matsuda, Ryosuke Suzuki, Hideki Aizaki, Fumio Sugawara, Takaji Wakita
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 440 Issue 4 Pg. 515-20 (Nov 01 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 24099774 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• Benzoates
• Biological Products
• Interferon-alpha
• Oligopeptides
• telaprevir
• sulochrin

Topics

• Antiviral Agents (pharmacology)
• Benzoates (chemistry, pharmacology)
• Biological Products (pharmacology)
• Cell Line
• Drug Synergism
• Hepacivirus (drug effects, physiology)
• Hepatocytes (virology)
• Humans
• Interferon-alpha (pharmacology)
• Oligopeptides (pharmacology)
• Penicillium (chemistry)
• Virus Internalization (drug effects)