Evaluation of a cyclophilin inhibitor in hepatitis C virus–infected chimeric mice in vivo

Authors

  • Kazuaki Inoue,

    Corresponding author
    1. Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
    2. Division of Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan
    • Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan
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    • These authors contributed equally to this work.

    • fax: (81) 3-3828-8945

  • Takuya Umehara,

    1. Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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    • These authors contributed equally to this work.

  • Urs T. Ruegg,

    1. Laboratory of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Switzerland
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  • Fumihiko Yasui,

    1. Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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  • Tsunamasa Watanabe,

    1. Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
    2. Division of Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan
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  • Hiroshi Yasuda,

    1. Division of Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan
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  • Jean-Maurice Dumont,

    1. Debiopharm SA Forum “après-demain” Chemin Messidor, Lausanne, Switzerland
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  • Pietro Scalfaro,

    1. Debiopharm SA Forum “après-demain” Chemin Messidor, Lausanne, Switzerland
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  • Makoto Yoshiba,

    1. Division of Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan
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  • Michinori Kohara

    1. Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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  • Potential conflict of interest: Dr. Ruegg received grants from Debiopharm.

Abstract

Cyclosporin A (CsA) inhibits replication of the HCV subgenomic replicon, and this effect is believed to not be mediated by its immunosuppressive action. We found that DEBIO-025, a novel non-immunosuppressive cyclophilin inhibitor derived from CsA, inhibited HCV replication in vitro more potently than CsA. We also examined the inhibitory effect of DEBIO-025 on naive HCV genotypes 1a or 1b in vivo using chimeric mice with human hepatocytes. These mice were treated for 14 days with DEBIO-025, pegylated-interferon α−2a (Peg-IFN), a combination of either drugs, or CsA in combination with Peg-IFN. In mice treated with Peg-IFN, serum HCV RNA levels decreased approximately 10-fold whereas DEBIO-025 treatment alone did not induce any significant change. In mice treated with both DEBIO-025 and Peg-IFN, HCV RNA levels decreased more than 100-fold. All mice treated with Peg-IFN combined with CsA died within 4 days. The combination treatment of DEBIO-025 and Peg-IFN reduced HCV RNA levels and core protein expression in liver, indicating that the HCV RNA levels reduction in serum was attributable to intrahepatic inhibition of HCV replication. Conclusion: We demonstrated that DEBIO-025 was better tolerated than CsA, and that its anti-HCV effect appeared to be synergistic in combination with Peg-IFN in vivo. (HEPATOLOGY 2007;45:921–928.)

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