title: ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo.
abstract: OBJECTIVE
  ME3738 (22β-methoxyolean-12-ene-3β, 24-diol), a derivative of soyasapogenol B, attenuates liver disease in several animal models of acute and chronic liver injury. ME3738 is thought to inhibit replication of hepatitis C virus (HCV) by enhancing interferon (IFN)-β production, as determined using the HCV full-length binary expression system. We examined the effect of ME3738 combined with IFN-α on HCV replication using the genotype 1b subgenomic replicon system and an in vivo mouse HCV model.
  
  
  METHODS
  HCV replicon cells (ORN/3-5B/KE cells and Con1 cells) were incubated with ME3738 and/or IFN-α, and then intracellular IFN-stimulated genes (ISGs) and HCV RNA replication were analyzed by reverse-transcription-real time polymerase chain reaction and luciferase reporter assay. HCV-infected human hepatocyte chimeric mice were also treated with ME3738 and/or IFN-α for 4 weeks. Mouse serum HCV RNA titer, HCV core antigen, and ISGs expression in the liver were measured.
  
  
  RESULTS
  ME3738 induced gene expression of oligoadenylate synthetase 1 and inhibited HCV replication in both HCV replicon cells. The drug enhanced the effect of IFN to significantly increase ISG expression levels, inhibit HCV replication in replicon cells, and reduce mouse serum HCV RNA and core antigen levels in mouse livers. The combination treatment was not hepatotoxic as evident histologically and did not reduce human serum albumin in mice.
  
  
  CONCLUSIONS
  ME3738 inhibited HCV replication, enhancing the effect of IFN-α to increase ISG expression both in vitro and in vivo, suggesting that the combination of ME3738 and IFN might be useful therapeutically for patients with chronic hepatitis C.
authors.affiliation: Department of Medicine and Molecular Science, Hiroshima University, Hiroshima-shi 734-8551, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.forename: Fukiko
authors.initials: F
authors.lastname: Mitsui
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Kawaoka
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Maekawa
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
authors.forename: Shoichi
authors.initials: S
authors.lastname: Murakami
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamashita
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuhira
authors.forename: Kenji
authors.initials: K
authors.lastname: Asai
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D001483:Base Sequence; D002460:Cell Line; D004195:Disease Models, Animal; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000637:transplantation / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000008:administration & dosage*; D051379:Mice; D016513:Mice, SCID; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D012367:RNA, Viral / Q000235:genetics; D011994:Recombinant Proteins; D012093:Replicon / Q000187:drug effects; D018183:Transplantation Chimera; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; C477463:ME3738; D012367:RNA, Viral; D011994:Recombinant Proteins; D009828:Oleanolic Acid