New preclinical antimalarial drugs potently inhibit hepatitis C virus genotype 1b RNA replication

• Published in: PloS one Vol. 8; no. 8; p. e72519
• Main Authors: Ueda, Youki, Takeda, Midori, Mori, Kyoko, Dansako, Hiromichi, Wakita, Takaji, Kim, Hye-Sook, Sato, Akira, Wataya, Yusuke, Ikeda, Masanori, Kato, Nobuyuki
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.08.2013; Public Library of Science (PLoS)
• Subjects: Anemia; Antimalarial agents; Antimalarials - analysis; Antimalarials - pharmacology; Assaying; Biology; Cell culture; Cell Line, Tumor; Cell lines; Chronic infection; Dentistry; Drug development; Drug Evaluation, Preclinical; Drug Synergism; Drugs; Exanthema; Gene expression; Genome, Viral - genetics; Genomes; Genotype; Genotype & phenotype; Global health; Hepacivirus - drug effects; Hepacivirus - genetics; Hepacivirus - physiology; Hepatitis; Hepatitis C; Hepatitis C virus; Humans; Infections; Informatics; Interferon; Interferon-alpha - pharmacology; Kinases; Kinetics; Liver; Liver diseases; Medicine; Pharmaceutical sciences; Plasmodium falciparum; Reagents; Replication; Ribavirin; Ribavirin - pharmacology; Ribonucleic acid; RNA; RNA viruses; RNA, Viral - metabolism; Skin; Taste disorders; Time Factors; Tocopherol; University graduates; Virology; Virus Replication - drug effects; Viruses; Vitamin E; Vitamin E - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072519

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.