Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs

Abstract

In light of the current outbreak of Ebola virus disease, there is an urgent need to develop effective therapeutics to treat Ebola infection, and drug repurposing screening is a potentially rapid approach for identifying such therapeutics. We developed a biosafety level 2 (BSL-2) 1536-well plate assay to screen for entry inhibitors of Ebola virus-like particles (VLPs) containing the glycoprotein (GP) and the matrix VP40 protein fused to a beta-lactamase reporter protein and applied this assay for a rapid drug repurposing screen of Food and Drug Administration (FDA)-approved drugs. We report here the identification of 53 drugs with activity of blocking Ebola VLP entry into cells. These 53 active compounds can be divided into categories including microtubule inhibitors, estrogen receptor modulators, antihistamines, antipsychotics, pump/channel antagonists, and anticancer/antibiotics. Several of these compounds, including microtubule inhibitors and estrogen receptor modulators, had previously been reported to be active in BSL-4 infectious Ebola virus replication assays and in animal model studies. Our assay represents a robust, effective and rapid high-throughput screen for the identification of lead compounds in drug development for the treatment of Ebola virus infection.

• Antipsychotics
• drug repurposing screen
• Ebola virus
• Ebola virus glycoprotein
• estrogen receptor modulator
• microtubule inhibitor
• virus entry
• VP40

The authors would like to thank the compound management group at NCATS, National Institutes of Health (NIH), for their professional support, as well as Richard Cadagan and Osman Lizardo for excellent technical support at the Icahn School of Medicine at Mount Sinai, New York, USA. This work was supported by the Intramural Research Program of the NCATS, and the NIH. Antiviral screen assays in Adolfo García-Sastre's lab are supported by NIH grants R01AI079110 and R01AI089539.

for this article can be found on Emerging Microbes & Infections's website (http://www.nature.com/emi/)