FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection.
FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection.
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DOI：
10.1126/scitranslmed.3005471
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发表时间：
2013-06-19
影响因子：
17.1
通讯作者：
Olinger GG
中科院分区：
文献类型：
--
作者：
Johansen LM;Brannan JM;Delos SE;Shoemaker CJ;Stossel A;Lear C;Hoffstrom BG;Dewald LE;Schornberg KL;Scully C;Lehár J;Hensley LE;White JM;Olinger GG
埃博拉病毒作为生物武器，在零星爆发期间以及受感染者可能从流行地区意外输入的情况下，仍然对平民和军人构成重大威胁。目前，尚无批准的疗法可以治疗或预防埃博拉病毒感染。因此，我们对美国食品药品监督管理局 (FDA) 和前美国批准的药物进行了体外筛选，并选择了分子探针来识别对扎伊尔埃博拉病毒 (EBOV) 模式物种具有抗病毒活性的药物。从这个筛选中，我们鉴定了一组选择性雌激素受体调节剂（SERM），包括克罗米芬和托瑞米芬，它们是埃博拉病毒感染的有效抑制剂。在小鼠体内感染模型中，这两种 SERM 均具有抗埃博拉病毒活性。即使在没有可检测到的雌激素受体表达的情况下，这种抗埃博拉病毒活性也会发生，并且两种 SERM 在内化后均抑制病毒进入，这表明克罗米芬和托瑞米芬并不是通过与雌激素受体相关的经典途径发挥作用。相反，这种反应似乎是一种脱靶效应，其中化合物干扰了病毒进入的后期步骤，并可能影响融合的触发。这些数据支持筛选现成的批准药物，以确定埃博拉病毒和其他传染病的治疗方法。本报告中描述的 SERM 化合物是一类可立即采取行动的批准药物，可重新用于治疗丝状病毒感染。
Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)– and ex–US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections.
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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：
11.4
作者：
Miller, Emily Happy;Obernosterer, Gregor;Chandran, Kartik
通讯作者：
Chandran, Kartik
影响因子：
5.4
作者：
Dube, Derek;Brecher, Matthew B.;White, Judith M.
通讯作者：
White, Judith M.
影响因子：
46.9
作者：
Lehar, Joseph;Krueger, Andrew S.;Avery, William;Heilbut, Adrian M.;Johansen, Lisa M.;Price, E. Roydon;Rickles, Richard J.;Short, Glenn F., III;Staunton, Jane E.;Jin, Xiaowei;Lee, Margaret S.;Zimmermann, Grant R.;Borisy, Alexis A.
通讯作者：
Borisy, Alexis A.
影响因子：
6.4
作者：
Bray, M;Davis, K;Huggins, J
通讯作者：
Huggins, J