A hepatitis C virus NS4B inhibitor suppresses viral genome replication by disrupting NS4B's dimerization/multimerization as well as its interaction with NS5A

Moonju Choi, Sungjin Lee, Taekyu Choi, Choongho Lee

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Chronic hepatitis C virus (HCV) infection is responsible for severe liver diseases including liver cirrhosis and hepatocellular carcinoma. An HCV non-structural protein 4B (NS4B) plays an essential role in viral RNA genome replication by building multi-vesicular structures around endoplasmic reticulum membranes. Especially, the second amphipathic helix of NS4B (NS4B-AH2) was shown to be essential for this process. By screening compounds against a membrane-aggregating activity of NS4B-AH2, several anti-HCV replication small molecules targeting NS4B-AH2 were discovered. However, little is known about detailed molecular mechanism of action for these NS4B-AH2 inhibitors. In this report, we provide evidences that NS4B-AH2 is required for NS4B's dimerization/multimerization, its proper subcellular localization, as well as its interaction with NS5A. More importantly, one of NS4B-AH2 inhibitors called "anguizole" was found to be able to disrupt all of these NS4B-AH2-mediated biological functions of NS4B. This newly elucidated mechanism of action will enable us not only to better understand a central role of NS4B-AH2 in HCV life cycle but also to develop a more safe and effective new class of NS4B-AH2 inhibitors of HCV replication in the future.

Original languageEnglish
Pages (from-to)395-407
Number of pages13
JournalVirus Genes
Volume47
Issue number3
DOIs
StatePublished - Dec 2013

Keywords

  • Amphipathic helix
  • Anguizole
  • Hepatitis C virus
  • Mechanism of action
  • NS4B dimerization/multimerization
  • NS4B inhibitor
  • NS4B subcellular localization
  • NS5A
  • RNA genome replication

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