Suppression of hepatitis C virus replication by cyclin-dependent kinase inhibitors

Tsubasa Munakata; Makoto Inada; Yuko Tokunaga; Takaji Wakita; Michinori Kohara; Akio Nomoto

doi:10.1016/j.antiviral.2014.05.011

Suppression of hepatitis C virus replication by cyclin-dependent kinase inhibitors

Antiviral Res. 2014 Aug:108:79-87. doi: 10.1016/j.antiviral.2014.05.011. Epub 2014 Jun 2.

Authors

Tsubasa Munakata¹, Makoto Inada², Yuko Tokunaga³, Takaji Wakita⁴, Michinori Kohara³, Akio Nomoto⁵

Affiliations

¹ Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: munakata-tb@igakuken.or.jp.
² Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
³ Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
⁴ Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
⁵ Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Institute of Microbial Chemistry, 3-14-23 Kamiohsaki, Shinagawa-ku, Tokyo 141-0021, Japan.

PMID: 24893207
DOI: 10.1016/j.antiviral.2014.05.011

Abstract

Hepatitis C virus (HCV) is a causative agent of chronic hepatitis. Although the standard therapy for HCV-infected patients consists of pegylated interferon plus ribavirin, this treatment is associated with serious side effects and high costs, and fails in some patients infected with specific HCV genotypes. To address this problem, we are developing small-molecule inhibitors of cyclin-dependent kinases (CDKs) as novel anti-HCV drug candidates. Previous data showed that HCV replication is inhibited by retinoblastoma protein, which is itself inactivated by CDK-mediated phosphorylation. Here, we report that CDK inhibitors suppress HCV replication in vitro and in vivo, and that CDK4 is required for efficient HCV replication. These findings shed light on the development of novel anti-HCV drugs that target host factors.

Keywords: CDK inhibitor; Chimera mice; HCV; Rb; Replicon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology*
Cell Line
Cyclin-Dependent Kinases / antagonists & inhibitors*
Drug Discovery / methods
Enzyme Inhibitors / pharmacology*
Hepacivirus / drug effects*
Hepacivirus / physiology*
Humans
Inhibitory Concentration 50
Virus Replication / drug effects*

Substances

Antiviral Agents
Enzyme Inhibitors
Cyclin-Dependent Kinases