Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA.
Viruses. 2010 Aug;2(8):1621-1634. doi: 10.3390/v2081621. Epub 2010 Aug 5.
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.
环孢素 A （Cyclophilin A，CyPA）在 HCV 复制中起着关键作用，越来越多的体外和体内证据支持这一观点。CyPA 可能通过其肽基脯氨酰顺反异构酶活性，直接与非结构蛋白 5A 相互作用，对 HCV 复制酶的适当结构和功能发挥作用。主要的脯氨酸底物位于 NS5A 的结构域 II 中，集中在一个“DY”二肽基序周围，该基序调节 CyPA 的依赖性和 CsA 的耐药性。重要的是，缺乏免疫抑制功能的环孢菌素 A 衍生物能有效地阻断 CyPA-NS5A 相互作用，并在细胞培养、动物模型和人类试验中抑制 HCV。鉴于耐药性的遗传屏障很高，并且它们的作用机制与当前的护理标准或任何针对 HCV 的特定靶向抗病毒治疗（STAT-C）不同，环孢素抑制剂有望成为一类新型的抗 HCV 治疗药物。
