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

Masanori Ikeda, Yoshinari Kawai, Kyoko Mori, Masahiko Yano, Ken ichi Abe, Go Nishimura, Hiromichi Dansako, Yasuo Ariumi, Takaji Wakita, Kazuhide Yamamoto, Nobuyuki Kato

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)871-880
Number of pages10
JournalLiver International
Volume31
Issue number6
DOIs
Publication statusPublished - Jul 2011

Fingerprint

geranylgeranylacetone
Anti-Ulcer Agents
Hepatitis C
Virus Replication
Hepacivirus
Hydroxymethylglutaryl-CoA Reductase Inhibitors
RNA
Prenylation
Therapeutics
Interferons
Protein Prenylation

Keywords

  • Geranylgeranylation
  • HCV
  • Selbex
  • Statin
  • Teprenone

ASJC Scopus subject areas

  • Hepatology

Cite this

Anti-ulcer agent teprenone inhibits hepatitis C virus replication : Potential treatment for hepatitis C. / Ikeda, Masanori; Kawai, Yoshinari; Mori, Kyoko; Yano, Masahiko; Abe, Ken ichi; Nishimura, Go; Dansako, Hiromichi; Ariumi, Yasuo; Wakita, Takaji; Yamamoto, Kazuhide; Kato, Nobuyuki.

In: Liver International, Vol. 31, No. 6, 07.2011, p. 871-880.

Research output: Contribution to journalArticle

Ikeda, M, Kawai, Y, Mori, K, Yano, M, Abe, KI, Nishimura, G, Dansako, H, Ariumi, Y, Wakita, T, Yamamoto, K & Kato, N 2011, 'Anti-ulcer agent teprenone inhibits hepatitis C virus replication: Potential treatment for hepatitis C', Liver International, vol. 31, no. 6, pp. 871-880. https://doi.org/10.1111/j.1478-3231.2011.02499.x
Ikeda, Masanori ; Kawai, Yoshinari ; Mori, Kyoko ; Yano, Masahiko ; Abe, Ken ichi ; Nishimura, Go ; Dansako, Hiromichi ; Ariumi, Yasuo ; Wakita, Takaji ; Yamamoto, Kazuhide ; Kato, Nobuyuki. / Anti-ulcer agent teprenone inhibits hepatitis C virus replication : Potential treatment for hepatitis C. In: Liver International. 2011 ; Vol. 31, No. 6. pp. 871-880.
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abstract = "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.",
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AU - Yano, Masahiko

AU - Abe, Ken ichi

AU - Nishimura, Go

AU - Dansako, Hiromichi

AU - Ariumi, Yasuo

AU - Wakita, Takaji

AU - Yamamoto, Kazuhide

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