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Viruses 2010, 2(8), 1621-1634; doi:10.3390/v2081621

Cyclophilin Inhibitors as a Novel HCV Therapy

Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA
Received: 17 June 2010 / Revised: 23 July 2010 / Accepted: 4 August 2010 / Published: 5 August 2010
(This article belongs to the Special Issue Antivirals Against Hepatitis C Virus)
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Abstract

A critical role of Cyclophilins, mostly Cyclophilin A (CyPA), in the replication of HCV is supported by a growing body of in vitro and in vivo evidence. CyPA probably interacts directly with nonstructural protein 5A to exert its effect, through its peptidyl-prolyl isomerase activity, on maintaining the proper structure and function of the HCV replicase. The major proline substrates are located in domain II of NS5A, centered around a “DY” dipeptide motif that regulates CyPA dependence and CsA resistance. Importantly, Cyclosporine A derivatives that lack immunosuppressive function efficiently block the CyPA-NS5A interaction and inhibit HCV in cell culture, an animal model, and human trials. Given the high genetic barrier to development of resistance and the distinctness of their mechanism from that of either the current standard of care or any specifically targeted antiviral therapy for HCV (STAT-C), CyP inhibitors hold promise as a novel class of anti-HCV therapy.
Keywords: Cyclophilins; Cyclosporine A; immunosuppression; nonstructural protein 5A/5B; HCV replication Cyclophilins; Cyclosporine A; immunosuppression; nonstructural protein 5A/5B; HCV replication
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Tang, H. Cyclophilin Inhibitors as a Novel HCV Therapy. Viruses 2010, 2, 1621-1634.

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