Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses.
Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses.
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DOI：
10.1016/j.antiviral.2013.03.023
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发表时间：
2013-06
影响因子：
7.6
通讯作者：
Block, Timothy M.
中科院分区：
文献类型：
--
作者：
Chang, Jinhong;Warren, Travis K.;Zhao, Xuesen;Gill, Tina;Guo, Fang;Wang, Lijuan;Comunale, Mary Ann;Du, Yanming;Alonzi, Dominic S.;Yu, Wenquan;Ye, Hong;Liu, Fei;Guo, Ju-Tao;Mehta, Anand;Cuconati, Andrea;Butters, Terry D.;Bavari, Sina;Xu, Xiaodong;Block, Timothy M.
宿主细胞内质网α-葡糖苷酶I和II对于使用钙连接蛋白介导的折叠途径的病毒糖基化包膜蛋白的成熟是必需的。这些聚糖加工酶的抑制导致这些病毒糖蛋白的错误折叠和降解以及随后病毒体分泌的减少。我们以前报道过，CM-10-18是一种亚氨基糖α-葡萄糖苷酶抑制剂，能有效地保护登革病毒感染小鼠的致死性。在当前的研究中，通过广泛的结构-活性关系研究，我们已经鉴定了三种CM-10-18衍生物，它们对引起出血热的四个病毒家族的代表性病毒表现出上级体外抗病毒活性。此外，这三种新型亚氨基糖显著降低了小鼠中两种最具致病性的出血热病毒马尔堡病毒和埃博拉病毒的死亡率。因此，我们的研究证明了这样的概念，即亚胺糖是有前途的候选药物，用于管理由各种病毒引起的病毒性出血热。
Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degradation of these viral glycoproteins and subsequent reduction in virion secretion. We previously reported that, CM-10-18, an imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivatives that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel imino sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that imino sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses.
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影响因子：
64.8
作者：
Cote, Marceline;Misasi, John;Ren, Tao;Bruchez, Anna;Lee, Kyungae;Filone, Claire Marie;Hensley, Lisa;Li, Qi;Ory, Daniel;Chandran, Kartik;Cunningham, James
通讯作者：
Cunningham, James
影响因子：
6.4
作者：
Kortepeter, Mark G.;Bausch, Daniel G.;Bray, Mike
通讯作者：
Bray, Mike
影响因子：
7.6
作者：
Chang, Jinhong;Schul, Wouter;Block, Timothy M.
通讯作者：
Block, Timothy M.
影响因子：
5.4
作者：
HE, JL;CHOE, S;LANDAU, NR
通讯作者：
LANDAU, NR
影响因子：
7.6
作者：
Chang, Jinhong;Schul, Wouter;Block, Timothy M.
通讯作者：
Block, Timothy M.