Cyclosporine A Inhibits Hepatitis C Virus Nonstructural Protein 2 Through Cyclophilin A
Cyclosporine A Inhibits Hepatitis C Virus Nonstructural Protein 2 Through Cyclophilin A
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DOI：
10.1002/hep.23281
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发表时间：
2009-11-01
期刊：
影响因子：
13.5
通讯作者：
Pietschmann, Thomas
中科院分区：
文献类型：
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作者：
Ciesek, Sandra;Steinmann, Eike;Pietschmann, Thomas
许多针对病毒非结构3 （NS3）蛋白酶或NS5B聚合酶的抗丙型肝炎病毒（HCV）药物目前正处于临床试验阶段。然而，快速耐药发展是一个主要问题，最佳治疗显然需要多种作用机制的结合。环孢素A （CsA）及其非免疫抑制剂衍生物是正在开发的更有前途的药物之一。基于对HCV亚基因组复制子的研究，人们认为它们的作用是ns5b抑制剂。在这项研究中，我们发现CsA抑制全长HCV日本暴发性肝炎（JFH1）基因组复制的效率比亚基因组复制子高约10倍。这种作用依赖于病毒多蛋白中NS2的存在，并通过细胞亲环蛋白a介导。NS2可能是csa依赖性抑制的额外靶点，也可能调节针对NS3至NS5B蛋白的抗病毒活性。因此，CsA是首个通过NS2起作用的抗hcv药物。结论：与亚基因组复制子相比，CsA通过靶向NS2/NS3连接的切割以及可能的其他非复制生命周期步骤，更有效地抑制JFH1全长基因组的复制。(肝脏病学50:1638 2009;1645)。
Numerous anti-hepatitis C virus (HCV) drugs targeting either the viral nonstructural 3 (NS3) protease or NS5B polymerase are currently in clinical testing. However, rapid resistance development is a major problem and optimal therapy will clearly require a combination of multiple mechanisms of action. Cyclosporine A (CsA) and its nonimmunosuppressant derivatives are among the more promising drugs under development. Based on work with subgenomic HCV replicons it has been thought that they act as NS5B-inhibitors. In this study we show that CsA inhibits replication of full-length HCV Japanese Fulminant Hepatitis (JFH1) genomes about 10-fold more efficiently than subgenomic replicons. This effect is dependent on the presence of NS2 in the viral polyprotein and mediated through cellular cyclophilin A. NS2 is either an additional target for CsA-dependent inhibition or modulates the antiviral activity against NS3 to NS5B proteins. CsA is thus the first anti-HCV drug shown to act through NS2. Conclusion: CsA inhibits replication of JFH1 full-length genomes much more efficiently than subgenomic replicons by targeting cleavage at the NS2/NS3 junction and possibly other nonreplication lifecycle steps. (HEPATOLOGY 2009;50:1638-1645.)