Hepatitis C virus replication is inhibited by 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738) through enhancing interferon-β

✍ Scribed by Yoichi Hiasa; Hiroyuki Kuzuhara; Yoshio Tokumoto; Ichiro Konishi; Nobuyuki Yamashita; Bunzo Matsuura; Kojiro Michitaka; Raymond T. Chung; Morikazu Onji

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 799 KB
• Volume: 48
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.22289

✦ Synopsis

A derivative of soyasapogenol, 22␤-methoxyolean-12-ene-3␤, 24(4␤)-diol (ME3738), ameliorates liver injury induced by Concanavalin A in mice. We examined whether ME3738 has independent antiviral effects against hepatitis C virus (HCV) using an established HCV replication model that expresses the full-length genotype 1a HCV complementary DNA plasmid (pT7-flHCV-Rz) under the control of a replication-defective adenoviral vector expressing T7 polymerase. Hepatocellular carcinoma (HepG2) cells, human hepatoma (Huh7) cells, or monkey kidney (CV-1) cells were transfected with pT7-flHCV-Rz, and infected with adenoviral vector expressing T7 polymerase. ME3738 or interferon-␣ (IFN-␣) was added thereafter and then protein and RNA were harvested from the cells at 9 days after infection. HCV-positive and HCV-negative strands were measured by real-time reversetranscription polymerase chain reaction and HCV core protein expression was measured using an enzyme-linked immunosorbent assay. The messenger RNA levels of innate antiviral response-related genes were assessed using real-time reverse-transcription polymerase chain reaction. ME3738 dose-dependently reduced HCV-RNA and core protein in hepatocytederived cell lines. The antiviral effect was more pronounced in HepG2 than in Huh7 cells. ME3738 increased messenger RNA levels of interferon-␤ (IFN-␤) and of IFN-stimulated genes (2-5 oligoadenylate synthetase, myxovirus resistance protein A [MxA]). Interferon-␤ knockdown by small interfering RNA abrogated the anti-HCV effect of ME3738. Moreover, the anti-HCV effects were synergistic when ME3738 was combined with IFN-␣. Conclusion: ME3738 has antiviral effects against HCV. The enhancement of autocrine IFN-␤ suggests that ME3738 exerts antiviral action along the type I IFN pathway. This anti-HCV action by ME3738 was synergistically enhanced when combined with IFN-␣. ME3738 might be a useful anti-HCV drug either with or without IFN-␣.