title: 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.affiliation: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. maikeda@md.okayama-u.ac.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Kawai
authors.forename: Kyoko
authors.initials: K
authors.lastname: Mori
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yano
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Abe
authors.forename: Go
authors.initials: G
authors.lastname: Nishimura
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Dansako
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ariumi
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
mesh_terms: D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017930:Genes, Reporter; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D054876:Prenylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012367:RNA, Viral / Q000096:biosynthesis*; D013997:Time Factors; D014162:Transfection; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000897:Anti-Ulcer Agents; D000998:Antiviral Agents; D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012367:RNA, Viral; D014764:Viral Proteins; D007371:Interferon-gamma; C031049:geranylgeranylacetone