Enhancing the antiviral potency of ER α-glucosidase inhibitor IHVR-19029 against hemorrhagic fever viruses in vitro and in vivo.
Enhancing the antiviral potency of ER α-glucosidase inhibitor IHVR-19029 against hemorrhagic fever viruses in vitro and in vivo.
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DOI：
10.1016/j.antiviral.2017.12.008
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发表时间：
2018-03
影响因子：
7.6
通讯作者：
Chang J
中科院分区：
文献类型：
--
作者：
Ma J;Zhang X;Soloveva V;Warren T;Guo F;Wu S;Lu H;Guo J;Su Q;Shen H;Solon E;Comunale MA;Mehta A;Guo JT;Bavari S;Du Y;Block TM;Chang J
靶向病毒复制所必需的宿主功能已被认为是广谱和耐药性难治的抗病毒方法。然而，到目前为止，只有少数宿主功能被验证为体内广谱抗病毒靶点。ER α-葡萄糖苷酶I和II已被证明对许多包膜病毒的形态发生至关重要，包括引起出血热的四个病毒家族的成员。已报告了各种基于亚胺糖的ER α-葡萄糖苷酶抑制剂在感染登革热、日本脑炎、埃博拉、马尔堡和流感病毒的动物中的体内抗病毒疗效。在本文中，我们使用CRISPR/Cas9建立了ER-α-葡萄糖苷酶I或II敲除的Huh7.5衍生细胞系，并证明登革热，黄热病和寨卡病毒的复制在敲除细胞系中仅减少1-2个对数。结果清楚地表明，通过其抑制剂完全抑制ER-α-葡糖苷酶I或II，可能仅部分抑制病毒复制。因此，我们探索通过与另一种广谱抗病毒药法匹拉韦（T-705）联合使用来提高先导亚氨基糖IHVR-19029的抗病毒疗效。事实上，IHVR-19029和T-705的组合可协同抑制黄热病和埃博拉病毒在培养细胞中的复制。此外，在埃博拉病毒感染的小鼠模型中，亚最佳剂量的IHVR-19029和T-705的组合显著增加了感染动物的存活率。因此，我们已经证明了用广谱宿主靶向和病毒靶向抗病毒药物治疗病毒性出血热的组合治疗策略的概念。
Targeting host functions essential for viral replication has been considered as a broad spectrum and resistance-refractory antiviral approach. However, only a few host functions have, thus far, been validated as broad-spectrum antiviral targets in vivo. ER α-glucosidases I and II have been demonstrated to be essential for the morphogenesis of many enveloped viruses, including members from four families of viruses causing hemorrhagic fever. In vivo antiviral efficacy of various iminosugar-based ER α-glucosidase inhibitors has been reported in animals infected with Dengue, Japanese encephalitis, Ebola, Marburg and influenza viruses. Herein, we established Huh7.5-derived cell lines with ER-α-glucosidase I or II knockout using CRISPR/Cas9 and demonstrated that the replication of Dengue, Yellow fever and Zika viruses was reduced by only 1–2 logs in the knockout cell lines. The results clearly indicate that only a partial suppression of viral replication can possibly be achieved with a complete inhibition of ER-α-glucosidases I or II by their inhibitors. We therefore explore to improve the antiviral efficacy of a lead iminosugar IHVR-19029 through combination with another broad-spectrum antiviral agent, favipiravir (T-705). Indeed, combination of IHVR-19029 and T-705 synergistically inhibited the replication of Yellow fever and Ebola viruses in cultured cells. Moreover, in a mouse model of Ebola virus infection, combination of sub-optimal doses of IHVR-19029 and T-705 significantly increased the survival rate of infected animals. We have thus proved the concept of combinational therapeutic strategy for the treatment of viral hemorrhagic fevers with broad spectrum host- and viral- targeting antiviral agents.
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影响因子：
5.4
作者：
Guo, Fang;Wu, Shuo;Chang, Jinhong
通讯作者：
Chang, Jinhong
影响因子：
7.6
作者：
Chang J;Block TM;Guo JT
通讯作者：
Guo JT
影响因子：
7.6
作者：
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通讯作者：
Barnard, Dale L.
影响因子：
13.2
作者：
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通讯作者：
Block, Timothy
影响因子：
7.6
作者：
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通讯作者：
Block, Timothy M.