Combinations of cyclophilin inhibitor NIM811 with hepatitis C virus NS3-4A protease or NS5B polymerase inhibitors enhance antiviral activity and suppress the emergence of resistance
Combinations of cyclophilin inhibitor NIM811 with hepatitis C virus NS3-4A protease or NS5B polymerase inhibitors enhance antiviral activity and suppress the emergence of resistance
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DOI：
10.1128/aac.00498-08
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发表时间：
2008-09-01
影响因子：
4.9
通讯作者：
Lin, Kai
中科院分区：
文献类型：
--
作者：
Mathy, Joanna E.;Ma, Sue;Lin, Kai
慢性丙型肝炎病毒（HCV）感染仍然是一个主要的全球健康负担，而目前基于干扰素的治疗是次优的。开发更有效的抗病毒药物的努力主要集中在两个病毒靶点：NS 3 -4A蛋白酶和NS 5 B聚合酶。然而，对这些病毒特异性抑制剂的耐药突变体在体外和患者中迅速出现，特别是在单药治疗的情况下。一种替代和补充策略是靶向宿主因子，如对病毒复制也必不可少的亲环素。未来的HCV治疗很可能是不同机制的多种药物的组合，以最大限度地提高抗病毒活性并抑制耐药性的出现。在此，使用HCV复制子在体外研究了将宿主亲环蛋白抑制剂NIM 811与其他病毒特异性抑制剂组合的效果。所有的组合导致比任何单一药剂更显著的抗病毒效果，而细胞毒性没有显著增加。此外，NIM 811与核苷（NM 107）或非核苷（噻吩-2-羧酸）聚合酶抑制剂的组合是协同的，而与蛋白酶抑制剂（BILN 2061）的组合是相加的。使用这些抑制剂在体外选择耐药克隆。有趣的是，对NIM 811产生耐药性比对病毒特异性抑制剂产生耐药性要困难得多。这些抑制剂之间没有观察到交叉耐药性。最值得注意的是，当与病毒蛋白酶或聚合酶抑制剂组合使用时，NIM 811在阻断耐药性的出现方面非常有效。综上所述，这些结果说明了联合靶向病毒和宿主因子的抑制剂作为未来HCV治疗的关键组成部分的显著优势。
Chronic hepatitis C virus (HCV) infection remains a major global health burden while current interferon-based therapy is suboptimal. Efforts to develop more effective antiviral agents mainly focus on two viral targets: NS3-4A protease and NS5B polymerase. However, resistant mutants against these viral specific inhibitors emerge quickly both in vitro and in patients, particularly in the case of monotherapy. An alternative and complementary strategy is to target host factors such as cyclophilins that are also essential for viral replication. Future HCV therapies will most likely be combinations of multiple drugs of different mechanisms to maximize antiviral activity and to suppress the emergence of resistance. Here, the effects of combining a host cyclophilin inhibitor NIM811 with other viral specific inhibitors were investigated in vitro using HCV replicon. All of the combinations led to more pronounced antiviral effects than any single agent, with no significant increase of cytotoxicity. Moreover, the combination of NIM811 with a nucleoside (NM107) or a non-nucleoside (thiophene-2-carboxylic acid) polymerase inhibitor was synergistic, while the combination with a protease inhibitor (BILN2061) was additive. Resistant clones were selected in vitro with these inhibitors. Interestingly, it was much more difficult to develop resistance against NIM811 than viral specific inhibitors. No cross-resistance was observed among these inhibitors. Most notably, NIM811 was highly effective in blocking the emergence of resistance when used in combination with viral protease or polymerase inhibitors. Taken together, these results illustrate the significant advantages of combining inhibitors targeting both viral and host factors as key components of future HCV therapies.