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 μM when it was determined by a reporter-based HCV replication assay, and the EC₅₀ was below 0.2 μM 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 μM 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.