Inhibitors of Endoplasmic Reticulum α-Glucosidases Potently Suppress Hepatitis C Virus Virion Assembly and Release
Inhibitors of Endoplasmic Reticulum α-Glucosidases Potently Suppress Hepatitis C Virus Virion Assembly and Release
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DOI：
10.1128/aac.01319-10
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发表时间：
2011-03-01
影响因子：
4.9
通讯作者：
Chang, Jinhong
中科院分区：
文献类型：
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作者：
Qu, Xiaowang;Pan, Xiaoben;Chang, Jinhong
α-葡糖苷酶I和II是内质网驻留酶，其对于N-连接聚糖加工和随后糖蛋白的正确折叠是必需的。在这份报告中，我们首先证明，下调α-葡萄糖苷酶I，II，或两者的表达在Huh7.5细胞中的小发夹RNA技术抑制丙型肝炎病毒（HCV）的生产。与α-葡糖苷酶在HCV包膜糖蛋白加工和折叠中的重要作用一致，用一组亚氨基糖衍生物（其为α-葡糖苷酶的竞争性抑制剂）治疗HCV感染的细胞不影响细胞内HCV RNA复制和非结构蛋白表达，但导致聚糖加工和随后的HCV E2糖蛋白降解的抑制。因此，HCV病毒体组装和分泌被抑制。在寻找具有更好抗病毒活性的亚氨基糖的过程中，我们发现一种新的亚氨基糖PBDNJ 0804具有上级抑制HCV病毒体组装和分泌的能力。综上所述，我们证明了葡萄糖苷酶是HCV感染的重要宿主因子为基础的抗病毒靶点。这种新型葡萄糖苷酶抑制剂出现耐药病毒的可能性较低，并且具有强效抗病毒功效，因此有望开发为治疗慢性丙型肝炎的治疗药物。
alpha-Glucosidases I and II are endoplasmic reticulum-resident enzymes that are essential for N-linked glycan processing and subsequent proper folding of glycoproteins. In this report, we first demonstrate that down-regulation of the expression of alpha-glucosidase I, II, or both in Huh7.5 cells by small hairpin RNA technology inhibited the production of hepatitis C virus (HCV). In agreement with the essential role of alpha-glucosidases in HCV envelope glycoprotein processing and folding, treatment of HCV-infected cells with a panel of imino sugar derivatives, which are competitive inhibitors of alpha-glucosidases, did not affect intracellular HCV RNA replication and nonstructural protein expression but resulted in the inhibition of glycan processing and subsequent degradation of HCV E2 glycoprotein. As a consequence, HCV virion assembly and secretion were inhibited. In searching for imino sugars with better antiviral activity, we found that a novel imino sugar, PBDNJ0804, had a superior ability to inhibit HCV virion assembly and secretion. In summary, we demonstrated that glucosidases are important host factor-based antiviral targets for HCV infection. The low likelihood of drug-resistant virus emergence and potent antiviral efficacy of the novel glucosidase inhibitor hold promise for its development as a therapeutic agent for the treatment of chronic hepatitis C.