Virus Genes

, Volume 47, Issue 3, pp 395–407

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
Article

DOI: 10.1007/s11262-013-0956-5

Cite this article as:
Choi, M., Lee, S., Choi, T. et al. Virus Genes (2013) 47: 395. doi:10.1007/s11262-013-0956-5

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.

Keywords

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

Abbreviations

HCV

Hepatitis C virus

NS4B

Non-structural protein 4B

AH

Amphipathic helix

NS4B-AH1

First amphipathic helix of NS4B

NS4B-AH2

Second amphipathic helix of NS4B

TM

Transmembrane

NS5A

Non-structural protein 5A

RC

Replication complex

ER

Endoplasmic reticulum

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Moonju Choi
    • 1
  • Sungjin Lee
    • 1
  • Taekyu Choi
    • 1
  • Choongho Lee
    • 1
  1. 1.College of PharmacyDongguk University-SeoulGoyangSouth Korea

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