Combinatorial screening of a panel of FDA-approved drugs identifies several candidates with anti-Ebola activities
Combinatorial screening of a panel of FDA-approved drugs identifies several candidates with anti-Ebola activities
复制标题
对 FDA 批准的一组药物进行组合筛选，确定了几种具有抗埃博拉活性的候选药物
DOI：
10.1016/j.bbrc.2019.11.065
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发表时间：
2020-02-19
影响因子：
3.1
通讯作者：
Qin, F. Xiao-Feng
中科院分区：
文献类型：
--
作者：
Du, Xiaohong;Zuo, Xiangyang;Qin, F. Xiao-Feng
Ebola virus (EBOV), pathogen of Ebola hemorrhagic fever (EHF), is an enveloped filamental RNA virus. Recently, the EHF crisis occurred in the Democratic Republic of the Congo again highlights the urgency for its clinical treatments. However, no Food and Drug Administration (FDA)-approved therapeutics are currently available. Drug repurposing screening is a time- and cost-effective approach for identifying anti-EBOV therapeutics. Here, by combinatorial screening using pseudovirion and minigenome replicon systems we have identified several FDA-approved drugs with significant anti-EBOV activities. These potential candidates include azithromycin, clomiphene, chloroquine, digitoxin, epigallocatechin-gallate, fluvastatin, tetrandrine and tamoxifen. Mechanistic studies revealed that fluvastatin inhibited EBOV pseudovirion entry by blocking the pathway of mevalonate biosynthesis, while the inhibitory effect of azithromycin on EBOV maybe due to its intrinsic cationic amphiphilic structure altering the homeostasis of later endosomal vesicle similar as tamoxifen. Moreover, based on structure and pathway analyses, the anti-EBOV activity has been extended to other family members of statins, such as simvastatin, and multiple other cardiac glycoside drugs, some of which exhibited even stronger activities. More importantly, in searching for drug interaction, we found various synergy between several anti-EBOV drug combinations, showing substantial and powerful synergistic against EBOV infection. In conclusion, our work illustrates a successful and productive approach to identify new mechanisms and targets for treating EBOV infection by combinatorial screening of FDA-approved drugs. (C) 2019 Published by Elsevier Inc.
