Inhibition of hepatitis C virus replication by arsenic trioxide.
Hepatitis C virus (HCV) is a serious global problem, and present therapeutics are inadequate to cure HCV infection. In the present study, various antiviral assays show that As2O3 at submicromolar concentrations is capable of inhibiting HCV replication. The 50% effective concentration (EC50) of As2O3 required to inhibit HCV replication was 0.35 microM when it was determined by a reporter-based HCV replication assay, and the EC50 was below 0.2 microM when it was determined by quantitative reverse transcription-PCR analysis. As2O3 did not cause cellular toxicity at this concentration, as revealed by an MTS [3-(4,5-dimethylthiozol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay. A combination of As2O3 and alpha interferon exerted synergistic effects against HCV, as revealed by a multiple linear logistic model and isobologram analysis. Furthermore, in an alternative HCV antiviral system that may recapitulate additional steps involved in HCV infection and replication, As2O3 at 0.3 microM totally abolished the HCV signal, whereas alpha interferon at a high dose (5,000 IU/ml) only partially suppressed the HCV signal. The study highlights the indications for use of a novel class of anti-HCV agent. Further elucidation of the exact antiviral mechanism of As2O3 may lead to the development of agents with potent activities against HCV or related viruses.
Hwang
Der-Ren
DR
Division of Biotechnology & Pharmaceutical Research, National Health Research Institutes, Taipei, Taiwan.
Tsai
Yuan-Chin
YC
Lee
Jin-Ching
JC
Huang
Kuo-Kuei
KK
Lin
Ren-Kuo
RK
Ho
Chia-Hua
CH
Chiou
Jeng-Min
JM
Lin
Ying-Ting
YT
Hsu
John T A
JT
Yeh
Chau-Ting
CT
D000998:Antiviral Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D017930:Genes, Reporter; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D010087:Oxides / Q000494:pharmacology*; D012367:RNA, Viral / Q000032:analysis / Q000096:biosynthesis; D012093:Replicon / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D001152:Arsenicals; D016898:Interferon-alpha; D010087:Oxides; D012367:RNA, Viral; D000077237:Arsenic Trioxide