Mizoribine inhibits hepatitis C virus RNA replication: effect of combination with interferon-alpha.
Interferon (IFN)-alpha monotherapy, as well as the more effective combination therapy of IFN-alpha 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 microM) 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-alpha and ribavirin exhibited more effective anti-HCV activity than the use of IFN-alpha alone. Moreover, we found that the anti-HCV activity of mizoribine in co-treatment with IFN-alpha was at least equivalent to that of ribavirin. This effect was apparent in the presence of at least 5 microM 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-alpha.
Naka
Kazuhito
K
Department of Molecular Biology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Ikeda
Masanori
M
Abe
Ken-ichi
K
Dansako
Hiromichi
H
Kato
Nobuyuki
N
D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D002999:Clone Cells / Q000821:virology; D017930:Genes, Reporter / Q000235:genetics; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000494:pharmacology*; D049410:Luciferases, Renilla / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis* / Q000235:genetics; D012254:Ribavirin / Q000494:pharmacology / Q000633:toxicity; D012263:Ribonucleosides / Q000494:pharmacology* / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012263:Ribonucleosides; D012254:Ribavirin; C010052:mizoribine; D049410:Luciferases, Renilla