Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811.
Hepatitis C virus (HCV) is a major causative agent of hepatocellular carcinoma. We recently discovered that the immunosuppressant cyclosporin A (CsA) and its analogue lacking immunosuppressive function, NIM811, strongly suppress the replication of HCV in cell culture. Inhibition of a cellular replication cofactor, cyclophilin (CyP) B, is critical for its anti-HCV effects. Here, we explored the potential use of CyP inhibitors for HCV treatment by analyzing the HCV replicon system. Treatment with CsA and NIM811 for 7 days reduced HCV RNA levels by 2-3 logs, and treatment for 3 weeks reduced HCV RNA to undetectable levels. NIM811 exerted higher anti-HCV activity than CsA at lower concentrations. Both CyP inhibitors rapidly reduced HCV RNA levels even further in combination with IFNalpha without modifying the IFNalpha signal transduction pathway. In conclusion, CyP inhibitors may provide a novel strategy for anti-HCV treatment.
Goto
Kaku
K
Laboratory of Human Tumor Viruses, Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Watashi
Koichi
K
Murata
Takayuki
T
Hishiki
Takayuki
T
Hijikata
Makoto
M
Shimotohno
Kunitada
K
D000998:Antiviral Agents / Q000494:pharmacology*; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D016898:Interferon-alpha / Q000494:pharmacology; D007700:Kinetics; D015398:Signal Transduction; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D021983:Cyclophilins