Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection.
Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection.
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DOI：
10.1038/nature10380
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发表时间：
2011-08-24
期刊：
影响因子：
64.8
通讯作者：
Cunningham, James
中科院分区：
文献类型：
--
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
埃博拉病毒(EBOV)是一种高致病性包膜病毒，在非洲引起人畜共患感染暴发。临床症状是感染后大量产生促炎细胞因子的表现，在许多疫情中，死亡率超过75%。发病不可预测、传播容易、疾病进展迅速、死亡率高以及缺乏有效的疫苗或治疗方法，引起了公众对EBOV的高度关注。在这里，我们报告了一种新的苯基哌嗪金刚烷二胺衍生化合物的鉴定，该化合物可以抑制EBOV感染。利用突变的细胞系和先导化合物的信息衍生物，我们证明了该抑制剂的靶标是内体膜蛋白Niemann-Pick C1(NPC1)。我们发现NPC1对感染是必不可少的，它与病毒糖蛋白(GP)结合，抗病毒化合物干扰GP与NPC1的结合。结合前人对GP结构和功能的研究结果，我们的发现支持EBOV感染的模型，在该模型中，内体组织蛋白酶切割GP1亚单位，去除严重糖基化的结构域，暴露N-末端结构域，N-末端结构域是NPC1的配体，并通过GP2亚单位调节膜融合。因此，NPC1是EBOV进入的关键，也是抗病毒治疗的靶点。
Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that the anti-viral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the N-terminal domain, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit. Thus, NPC1 is essential for EboV entry and a target for anti-viral therapy.
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影响因子：
6.7
作者：
Towner, Jonathan S.;Sealy, Tara K.;Khristova, Marina L.;Albarino, Cesar G.;Conlan, Sean;Reeder, Serena A.;Quan, Phenix-Lan;Lipkin, W. Ian;Downing, Robert;Tappero, Jordan W.;Okware, Samuel;Lutwama, Julius;Bakamutumaho, Barnabas;Kayiwa, John;Comer, James A.;Rollin, Pierre E.;Ksiazek, Thomas G.;Nichol, Stuart T.
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White, Judith M.
影响因子：
5.4
作者：
Hood, Chantelle L.;Abraham, Jonathan;Nabel, Gary J.
通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Grinstein, Sergio
影响因子：
8.8
作者：
Weidmann, M;M端hlberger, E;Hufert, FT
通讯作者：
Hufert, FT