Steinmann Eike, Whitfield Thomas, Kallis Stephanie, Dwek Raymond A, Zitzmann Nicole, Pietschmann Thomas, Bartenschlager Ralf
Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany.
Hepatology. 2007 Aug;46(2):330-8. doi: 10.1002/hep.21686.
Current therapy of chronic hepatitis C is based on the combination of pegylated interferon-alpha and ribavirin. In spite of 50% sustained virological response, therapy is still limited by unsatisfying success rates with genotype 1 infections and adverse side effects. One attempt to increase success rates is triple combination therapy of interferon and ribavirin with amantadine, a drug assumed to interfere with HCV p7 ion channel function. However, results from clinical trials indicate limited efficacy and the antiviral activity is unclear. In contrast, NS3 protease inhibitors have shown potent antiviral effects in clinical trials but rapid selection for drug resistance may limit their benefit. Targeting cellular factors required for HCV is therefore an attractive alternative. In this study, employing a system for production of infectious HCV particles in cell culture, we determined the antiviral effects of amantadine and iminosugar derivatives; the second of which primarily target host cell glucosidases required for folding and maturation of HCV envelope glycoproteins. We found that across a spectrum of HCV isolates and genotypes, amantadine affected neither RNA replication nor the release or infectivity of HCV particles. In agreement, p7 ion channel activity was not affected by amantadine, demonstrating that amantadine is not an HCV-selective antiviral. In contrast, a dose-dependent reduction of virus titers was achieved with iminosugars. Furthermore, HCV was rapidly eliminated from cell culture upon passage in the presence of a long alkyl chain deoxynojirimycin (DNJ).
Iminosugar derivatives are potential drugs for treatment of HCV infections.
目前慢性丙型肝炎的治疗基于聚乙二醇化干扰素-α和利巴韦林的联合使用。尽管有50%的持续病毒学应答，但治疗仍受限于1型感染的成功率不尽人意以及不良副作用。提高成功率的一种尝试是干扰素、利巴韦林与金刚烷胺的三联联合疗法，金刚烷胺被认为可干扰丙型肝炎病毒（HCV）p7离子通道功能。然而，临床试验结果显示疗效有限且抗病毒活性尚不明确。相比之下，NS3蛋白酶抑制剂在临床试验中已显示出强大的抗病毒作用，但对耐药性的快速选择可能会限制其益处。因此，靶向HCV所需的细胞因子是一种有吸引力的替代方法。在本研究中，我们利用细胞培养中生产传染性HCV颗粒的系统，确定了金刚烷胺和亚氨基糖衍生物的抗病毒作用；后者主要靶向HCV包膜糖蛋白折叠和成熟所需的宿主细胞糖苷酶。我们发现，在一系列HCV分离株和基因型中，金刚烷胺既不影响RNA复制，也不影响HCV颗粒的释放或感染性。同样，p7离子通道活性不受金刚烷胺影响，这表明金刚烷胺不是一种HCV选择性抗病毒药物。相比之下，亚氨基糖可使病毒滴度呈剂量依赖性降低。此外，在存在长烷基链脱氧野尻霉素（DNJ）的情况下传代时，HCV可从细胞培养物中迅速清除。
亚氨基糖衍生物是治疗HCV感染的潜在药物。
