Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus
Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus
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DOI：
10.1002/hep.21686
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发表时间：
2007-08-01
期刊：
影响因子：
13.5
通讯作者：
Bartenschlager, Ralf
中科院分区：
文献类型：
--
作者：
Steinmann, Eike;Whitfield, Thomas;Bartenschlager, Ralf
目前慢性丙型肝炎的治疗是基于聚乙二醇化干扰素-a和利巴韦林的联合治疗。尽管有50%的持续病毒学应答，但治疗仍然受到1型感染成功率和不良副作用的限制。提高成功率的一种尝试是干扰素和利巴韦林与金刚烷胺的三联疗法，金刚烷胺被认为是一种干扰丙型肝炎病毒p7离子通道功能的药物。然而，临床试验结果表明疗效有限，抗病毒活性尚不清楚。相比之下，NS3蛋白酶抑制剂在临床试验中显示出强大的抗病毒作用，但快速选择抗药性可能会限制它们的益处。因此，靶向丙型肝炎病毒所需的细胞因子是一个有吸引力的替代方案。在这项研究中，我们使用了一个在细胞培养中生产具有感染性的丙型肝炎病毒颗粒的系统，我们确定了金刚烷胺和亚胺糖衍生物的抗病毒作用；第二种衍生物主要针对宿主细胞中折叠和成熟丙型肝炎病毒包膜糖蛋白所需的葡萄糖苷酶。我们发现，在一系列丙型肝炎病毒分离株和基因型别中，金刚烷胺既不影响RNA复制，也不影响丙型肝炎病毒颗粒的释放或传染性。一致认为，金刚烷胺不影响p7离子通道活性，表明金刚烷胺不是一种丙型肝炎病毒选择性抗病毒药物。相比之下，使用亚胺糖可以实现剂量依赖性的病毒滴度降低。此外，在长烷基链脱氧野生霉素(DNJ)存在的情况下，丙型肝炎病毒在传代后迅速从细胞培养中消除。结论：亚胺糖衍生物是治疗丙型肝炎病毒感染的潜在药物。
Current therapy of chronic hepatitis C is based on the combination of pegylated interferon-a 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). Conclusion: Iminosugar derivatives are potential drugs for treatment of HCV infections.