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

• Published in: Liver international Vol. 31; no. 6; pp. 871 - 880
• Main Authors: Ikeda, Masanori, Kawai, Yoshinari, Mori, Kyoko, Yano, Masahiko, Abe, Ken-ichi, Nishimura, Go, Dansako, Hiromichi, Ariumi, Yasuo, Wakita, Takaji, Yamamoto, Kazuhide, Kato, Nobuyuki
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2011
• Subjects: Anti-Ulcer Agents - pharmacology; Antiviral Agents - pharmacology; Cell Line, Tumor; Diterpenes - pharmacology; Dose-Response Relationship, Drug; Drug Synergism; Genes, Reporter; geranylgeranylation; HCV; Hepacivirus - drug effects; Hepacivirus - genetics; Hepacivirus - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - virology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Interferon-gamma - pharmacology; Prenylation; Protein Processing, Post-Translational - drug effects; RNA, Viral - biosynthesis; Selbex; statin; teprenone; Time Factors; Transfection; Viral Proteins - metabolism; Virus Replication - drug effects
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/j.1478-3231.2011.02499.x

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 K2 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.