NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon
NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon
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DOI：
10.1128/aac.00310-06
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发表时间：
2006-09-01
影响因子：
4.9
通讯作者：
Lin, Kai
中科院分区：
文献类型：
--
作者：
Ma, Sue;Boerner, Joanna E.;Lin, Kai
参与病毒复制的宿主因子是潜在的有吸引力的抗病毒靶点，与病毒酶的特异性抑制剂互补，因为在长期治疗期间可能出现针对后者的耐药突变。近年来有报道称，环孢菌素可与亲环蛋白家族结合，在体外抑制丙型肝炎病毒（HCV）的复制。在此，在HCV复制子系统中评价了各种环孢菌素衍生物的活性。这些化合物的抗HCV活性和亲环素结合亲和力之间存在很强的相关性。其中，NIM811已被选为HCV感染的治疗候选物，因为它以比环孢菌素更高的亲和力结合亲环素，但缺乏与环孢菌素相关的显著免疫抑制活性。NIM811诱导复制子细胞中HCV RNA浓度依赖性减少，48小时时50%抑制浓度为0.66 μ M。此外，在用低至1 μ M的NIM 811处理细胞9天后，实现了大于三个对数的病毒RNA减少。此外，NIM811与α干扰素的组合显著增强抗HCV活性而不引起细胞毒性的任何增加。总之，这些有希望的体外数据保证了NIM 811（一种新机制的抑制剂）治疗丙型肝炎的临床研究。
Host factors involved in viral replication are potentially attractive antiviral targets that are complementary to specific inhibitors of viral enzymes, since resistant mutations against the latter are likely to emerge during long-term treatment. It has been reported recently that cyclosporine, which binds to a family of cellular proteins, cyclophilins, inhibits hepatitis C virus (HCV) replication in vitro. Here, the activities of various cyclosporine derivatives were evaluated in the HCV replicon system. There was a strong correlation between the anti-HCV activity and cyclophilin-binding affinity of these compounds. Of these, NIM811 has been selected as a therapeutic candidate for HCV infection, since it binds to cyclophilins with higher affinity than cyclosporine but is devoid of the significant immunosuppressive activity associated with cyclosporine. NIM811 induced a concentration-dependent reduction of HCV RNA in the replicon cells with a 50% inhibitory concentration of 0.66 mu M at 48 h. Furthermore, a greater than three-log,, viral RNA reduction was achieved after treating the cells with as little as 1 mu M of NIM811 for 9 days. In addition, the combination of NIM811 with alpha interferon significantly enhanced anti-HCV activities without causing any increase of cytotoxicity. Taken together, these promising in vitro data warrant clinical investigation of NIM811, an inhibitor of novel mechanism, for the treatment of hepatitis C.