In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus
In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus
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DOI：
10.1172/jci200317704
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发表时间：
2003-08-01
影响因子：
15.9
通讯作者：
Glenn, JS
中科院分区：
文献类型：
--
作者：
Bordier, BB;Ohkanda, J;Glenn, JS
丁型肝炎病毒（HDV）可使合并感染B型肝炎病毒（HBV）的患者的肝脏疾病显著恶化。对于HDV没有有效的药物治疗。HDV包膜需要由HBV提供的HBV表面抗原蛋白。然而，一旦进入细胞，HDV可以在没有任何HBV基因产物的情况下复制其基因组。在体外，HDV病毒粒子组装严重依赖于其核衣壳样蛋白大δ抗原的异戊二烯基脂质修饰或异戊二烯化。为了克服目前动物模型的局限性，并检验药理学异戊二烯化抑制可以防止体内HDV病毒体产生的假设，我们建立了一种方便的基于小鼠的能够产生病毒血症的HDV感染模型。然后用异戊烯化抑制剂FTI-277和FTI-2153处理这些小鼠。两种药物在清除HDV病毒血症方面都非常有效。正如预期，HDV抑制表现出治疗持续时间依赖性。这些结果提供了第一个临床前数据，支持异戊二烯化抑制作为一种新型抗病毒治疗的体内疗效，具有潜在的应用HDV和各种其他病毒。
Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses.