title: New preclinical antimalarial drugs potently inhibit hepatitis C virus genotype 1b RNA replication.
abstract: Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed.
  
  
  
  Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8) were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251) showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-α demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-α-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-α and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect.
  
  
  
  We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.
authors.affiliation: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan.
authors.forename: Youki
authors.initials: Y
authors.lastname: Ueda
authors.forename: Midori
authors.initials: M
authors.lastname: Takeda
authors.forename: Kyoko
authors.initials: K
authors.lastname: Mori
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Dansako
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Wataya
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
mesh_terms: D000962:Antimalarials / Q000032:analysis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D016679:Genome, Viral / Q000235:genetics; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D012367:RNA, Viral / Q000378:metabolism*; D012254:Ribavirin / Q000494:pharmacology; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D016898:Interferon-alpha; D012367:RNA, Viral; D014810:Vitamin E; D012254:Ribavirin
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