Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen

• Published in: Nature medicine Vol. 22; no. 10; pp. 1101 - 1107
• Main Authors: Xu, Miao, Lee, Emily M, Wen, Zhexing, Cheng, Yichen, Huang, Wei-Kai, Qian, Xuyu, TCW, Julia, Kouznetsova, Jennifer, Ogden, Sarah C, Hammack, Christy, Jacob, Fadi, Nguyen, Ha Nam, Itkin, Misha, Hanna, Catherine, Shinn, Paul, Allen, Chase, Michael, Samuel G, Simeonov, Anton, Huang, Wenwei, Christian, Kimberly M, Goate, Alison, Brennand, Kristen J, Huang, Ruili, Xia, Menghang, Ming, Guo-li, Zheng, Wei, Song, Hongjun, Tang, Hengli
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2016; Nature Publishing Group
• Subjects: 631/154/1435/2163; 631/378/1689/2608; Anthelmintic agents; Antiparasitic agents; Antiviral agents; Apoptosis; Astrocytes; Astrocytes - drug effects; Biomedicine; Brain - drug effects; Cancer Research; Caspase 3 - drug effects; Caspase inhibitors; Caspase Inhibitors - pharmacology; Caspase-3; Cell death; Cell Death - drug effects; Cell Line; Cortex; Diagnosis; Dosage and administration; Drug development; Drug Repositioning; Drug therapy; Emergency response; FDA approval; Global health; Humans; Induced Pluripotent Stem Cells - drug effects; Infections; Infectious Diseases; Inhibitors; Kinases; Lead compounds; Metabolic Diseases; Microcephaly - prevention & control; Microencephaly; Molecular Medicine; Neural stem cells; Neural Stem Cells - drug effects; Neurons - drug effects; Neuroprotection; Neurosciences; Niclosamide; Niclosamide - pharmacology; Organoids; Outbreaks; Pentanoic Acids - pharmacology; Pharmacology; Replication; Testing; Vector-borne diseases; Virus Replication - drug effects; Viruses; Zika virus; Zika Virus - drug effects; Zika virus infection; Zika Virus Infection - drug therapy
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.4184

A high-throughput screen of preclinical, investigational and FDA-approved drugs identifies compounds that possess antiviral and neuroprotective effects against Zika virus infection in human neural progenitor cells and astrocytes. In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.