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

Hepatology. 2007 Apr;45(4):921-8. doi: 10.1002/hep.21587.

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 alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Cyclophilins / antagonists & inhibitors*
  • Cyclosporine / pharmacology
  • Cyclosporine / therapeutic use*
  • Genotype
  • Hepacivirus / genetics
  • Hepatitis C / drug therapy*
  • Humans
  • Immunohistochemistry
  • Immunosuppression
  • Interferon alpha-2
  • Interferon-alpha / pharmacology
  • Interferon-alpha / therapeutic use*
  • Mice
  • Mice, SCID
  • Polyethylene Glycols / pharmacology
  • Polyethylene Glycols / therapeutic use*
  • RNA, Viral / drug effects*
  • RNA, Viral / metabolism
  • Recombinant Proteins
  • Replicon / drug effects
  • Serum Albumin
  • Transplantation Chimera
  • Viral Core Proteins / metabolism

Substances

  • Antiviral Agents
  • Interferon alpha-2
  • Interferon-alpha
  • RNA, Viral
  • Recombinant Proteins
  • Serum Albumin
  • Viral Core Proteins
  • Polyethylene Glycols
  • Cyclosporine
  • Cyclophilins
  • peginterferon alfa-2a
  • alisporivir