Anti-ulcer agent teprenone inhibits hepatitis C virus replication: potential treatment for hepatitis C.

Abstract

BACKGROUND:

Previously we reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, inhibited hepatitis C virus (HCV) RNA replication. Furthermore, recent reports revealed that the statins are associated with a reduced risk of hepatocellular carcinoma and lower portal pressure in patients with cirrhosis. The statins exhibited anti-HCV activity by inhibiting geranylgeranylation of host proteins essential for HCV RNA replication. Geranylgeranyl pyrophosphate (GGPP) is a substrate for geranylgeranyltransferase. Therefore, we examined the potential of geranyl compounds with chemical structures similar to those of GGPP to inhibit HCV RNA replication.

METHODS:

We tested geranyl compounds [geranylgeraniol, geranylgeranoic acid, vitamin K(2) and teprenone (Selbex)] for their effects on HCV RNA replication using genome-length HCV RNA-replicating cells (the OR6 assay system) and a JFH-1 infection cell culture system. Teprenone is the major component of the anti-ulcer agent, Selbex. We also examined the anti-HCV activities of the geranyl compounds in combination with interferon (IFN)-α or statins.

RESULTS:

Among the geranyl compounds tested, only teprenone exhibited anti-HCV activity at a clinically achievable concentration. However, other anti-ulcer agents tested had no inhibitory effect on HCV RNA replication. The combination of teprenone and IFN-α exhibited a strong inhibitory effect on HCV RNA replication. Although teprenone alone did not inhibit geranylgeranylation, surprisingly, statins' inhibitory action against geranylgeranylation was enhanced by cotreatment with teprenone.

CONCLUSIONS:

The anti-ulcer agent teprenone inhibited HCV RNA replication and enhanced statins' inhibitory action against geranylgeranylation. This newly discovered function of teprenone may improve the treatment of HCV-associated liver diseases as an adjuvant to statins.

• Authors: Masanori Ikeda, Yoshinari Kawai, Kyoko Mori, Masahiko Yano, Ken-ichi Abe, Go Nishimura, Hiromichi Dansako, Yasuo Ariumi, Takaji Wakita, Kazuhide Yamamoto, Nobuyuki Kato
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 31 Issue 6 Pg. 871-80 (Jul 2011) ISSN: 1478-3231 [Electronic] United States
• PMID: 21645219 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 John Wiley & Sons A/S.

Chemical References

• Anti-Ulcer Agents
• Antiviral Agents
• Diterpenes
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• RNA, Viral
• Viral Proteins
• Interferon-gamma
• geranylgeranylacetone

Topics

• Anti-Ulcer Agents (pharmacology)
• Antiviral Agents (pharmacology)
• Cell Line, Tumor
• Diterpenes (pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Genes, Reporter
• Hepacivirus (drug effects, genetics, metabolism)
• Hepatocytes (drug effects, metabolism, virology)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Interferon-gamma (pharmacology)
• Prenylation
• Protein Processing, Post-Translational (drug effects)
• RNA, Viral (biosynthesis)
• Time Factors
• Transfection
• Viral Proteins (metabolism)
• Virus Replication (drug effects)