1. Academic Validation
  2. 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

  • Biochem Biophys Res Commun. 2020 Feb 19;522(4):862-868. doi: 10.1016/j.bbrc.2019.11.065.
Xiaohong Du 1 Xiangyang Zuo 1 Fang Meng 1 Fei Wu 1 Xin Zhao 1 Chunfeng Li 1 Genhong Cheng 2 F Xiao-Feng Qin 3
Affiliations

Affiliations

  • 1 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China.
  • 2 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA.
  • 3 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China. Electronic address: fqin1@foxmail.com.
Abstract

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.

Keywords

Azithromycin; Cardiac glycoside; Drug repurposing; EBOV; FDA-Approved drugs; Statin.

Figures
Products