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


CONCLUSIONS
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.
Inoue
Kazuaki
K
Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. kinoue@rinshoken.or.jp
Umehara
Takuya
T
Ruegg
Urs T
UT
Yasui
Fumihiko
F
Watanabe
Tsunamasa
T
Yasuda
Hiroshi
H
Dumont
Jean-Maurice
JM
Scalfaro
Pietro
P
Yoshiba
Makoto
M
Kohara
Michinori
M
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D012367:RNA, Viral / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins; D012093:Replicon / Q000187:drug effects; D012709:Serum Albumin; D018183:Transplantation Chimera; D014758:Viral Core Proteins / Q000378:metabolism
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D012709:Serum Albumin; D014758:Viral Core Proteins; D011092:Polyethylene Glycols; D016572:Cyclosporine; D021983:Cyclophilins; C100416:peginterferon alfa-2a; C499715:alisporivir