ID | 53955 |
FullText URL | |
Author |
Ueda, Youki
Takeda, Midori
Mori, Kyoko
Wakita, Takaji
Sato, Akira
Wataya, Yusuke
Ikeda, Masanori
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Abstract | BACKGROUND:
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.
METHODOLOGY/PRINCIPAL FINDINGS:
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.
CONCLUSIONS/SIGNIFICANCE:
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.
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Note | This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Published Date | 2013-08-30
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Publication Title |
PLOS ONE
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Volume | volume8
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Issue | issue8
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Publisher | PUBLIC LIBRARY SCIENCE
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Start Page | e72519
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ISSN | 1932-6203
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Content Type |
Journal Article
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Official Url | http://dx.doi.org/10.1371/journal.pone.0072519
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Related Url | http://ousar.lib.okayama-u.ac.jp/metadata/53390
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language |
English
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Copyright Holders | © 2013 Ueda et al.
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File Version | publisher
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Refereed |
True
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DOI | |
PubMed ID | |
Web of Science KeyUT |