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Antimicrobial Agents and Chemotherapy, August 2004, p. 2876-2882, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2876-2882.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Hepatitis C Virus Replication by Arsenic Trioxide

Division of Biotechnology and Pharmaceutical Research,¹ Division of Biostatistics and Bioinformatics, National Health Research Institutes,² Liver Research Unit, Chang Gung Memorial Hospital, Taipei,⁴ Department of Chemical Engineering, National Tsing Hua Unversity, Hsinchu, Taiwan³

Received 16 September 2003/ Returned for modification 13 November 2003/ Accepted 29 March 2004

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.

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