Ciesek Sandra, Steinmann Eike, Wedemeyer Heiner, Manns Michael P, Neyts Johann, Tautz Norbert, Madan Vanesa, Bartenschlager Ralf, von Hahn Thomas, Pietschmann Thomas
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
Hepatology. 2009 Nov;50(5):1638-45. doi: 10.1002/hep.23281.
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.
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.
目前，众多靶向病毒非结构蛋白3（NS3）蛋白酶或NS5B聚合酶的抗丙型肝炎病毒（HCV）药物正处于临床试验阶段。然而，快速产生耐药性是一个主要问题，最佳治疗方案显然需要多种作用机制联合使用。环孢素A（CsA）及其非免疫抑制衍生物是正在研发的较有前景的药物之一。基于对亚基因组HCV复制子的研究，人们认为它们可作为NS5B抑制剂。在本研究中，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抑制亚基因组复制子高约10倍。这种效应取决于病毒多聚蛋白中NS2的存在，并通过细胞亲环蛋白A介导。NS2要么是CsA依赖性抑制的另一个靶点，要么调节针对NS3至NS5B蛋白的抗病毒活性。因此，CsA是首个被证明通过NS2发挥作用的抗HCV药物。
CsA通过靶向NS2/NS3连接处的切割以及可能的其他非复制生命周期步骤，比抑制亚基因组复制子更有效地抑制JFH1全长基因组的复制。
