Mizoribine inhibits hepatitis C virus RNA replication: Effect of combination with interferon-α

Interferon (IFN)-α monotherapy, as well as the more effective combination therapy of IFN-α and ribavirin, are currently used for patients with chronic hepatitis C caused by hepatitis C virus (HCV) infection, although the mechanisms of the antiviral effects of these reagents on HCV remain ambiguous, and side effects such as anemia due to the administration of ribavirin present a problem for patients who are advanced in years. Using a recently developed reporter assay system in which genome-length dicistronic HCV RNA encoding Renilla luciferase gene was found to replicate efficiently, we found that mizoribine, an imidazole nucleoside, inhibited HCV RNA replication. The anti-HCV activity of mizoribine (IC50: approximately 100 μM) was similar to that of ribavirin. Using this genome-length HCV RNA replication monitor system, we were the first to demonstrate that the combination of IFN-α and ribavirin exhibited more effective anti-HCV activity than the use of IFN-α alone. Moreover, we found that the anti-HCV activity of mizoribine in co-treatment with IFN-α was at least equivalent to that of ribavirin. This effect was apparent in the presence of at least 5 μM mizoribine. Since mizoribine is currently used in several clinical applications and has not been associated with severe side effects, mizoribine is considered to be of potential use as a new anti-HCV reagent in combination with IFN-α.