title: Inhibition of hepatitis C virus replication by antimonial compounds.
abstract: Chronic hepatitis C virus (HCV) infection is a worldwide health problem causing serious complications, such as liver cirrhosis and hepatoma. Alpha interferon (IFN-alpha) or its polyethylene glycol-modified form combined with ribavirin is the only recommended therapy. However, an alternative therapy is needed due to the unsatisfactory cure rate of the IFN-based therapy. Using a modified reporter assay based on the HCV subgenomic-replicon system, we found that sodium stibogluconate (SSG), a compound used for leishmania treatment, suppressed HCV replication. We have previously reported that SSG is effective at inhibiting HCV replication in a cell line permissive for HCV infection/replication and in an ex vivo assay using fresh human liver slices obtained from patients infected with HCV (26). In this study, we show that the SSG 50% inhibitory dose for HCV replication is 0.2 to 0.3 mg/ml (equivalent to 345 to 517 microM of Sb) in the HCV subgenomic-replicon system. We also found that SSG and IFN-alpha exert a strong synergistic anti-HCV effect in both the traditional isobologram analysis and the median effect principle (CalcuSyn analysis). The combination of SSG and IFN-alpha could sustain the antiviral response better than SSG or IFN-alpha alone. The results suggest that SSG may be a good drug candidate for use in combination with other therapeutics, such as IFN-alpha and ribavirin, to treat HCV infection.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, Republic of China.
authors.forename: Der-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Ren-Kuo
authors.initials: RK
authors.lastname: Lin
authors.forename: Guang-Zhou
authors.initials: GZ
authors.lastname: Leu
authors.forename: Tiao-Yin
authors.initials: TY
authors.lastname: Lin
authors.forename: Tzu-Wen
authors.initials: TW
authors.lastname: Lien
authors.forename: Ming-Chen
authors.initials: MC
authors.lastname: Yu
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
mesh_terms: D000965:Antimony / Q000494:pharmacology*; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D002712:Chlorides / Q000494:pharmacology*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008113:Liver Neoplasms / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D002712:Chlorides; D049452:Green Fluorescent Proteins; D000965:Antimony; D008156:Luciferases; C054672:antimony trichloride; C037554:antimony trioxide; D000967:Antimony Sodium Gluconate