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

• Type of Material: Article
• Authors: Miao Xu, National Institutes of Health; Emily M. Lee, Florida State University; Zhexing Wen, Emory University; Yichen Cheng, Florida State University; Wei-Kai Huang, The Johns Hopkins School of Medicine; Xuyu Qian, The Johns Hopkins School of Medicine; Julia TCW, Icahn School of Medicine at Mount Sinai; Jennifer Kouznetsova, National Institutes of Health; Sarah C. Ogden, Florida State University; Christy Hammack, Florida State University
• Language: English
• Date: 2016-10
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Nature America, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nm.4184
• Title of Journal or Parent Work: Nature Medicine
• ISSN: 1078-8956
• Volume: 22
• Issue: 10
• Start Page: 1101
• End Page: 1107
• Grant/Funding Information: This work was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH) (W.Z.); by ZIKV seed funding from Florida State University (H.T.), Start-up fund from Emory University (Z.W.), Brain and Behavior Research Foundation and the New York Stem Cell Foundation (K.J.B.), Maryland Stem Cell Research Fund (G-l.M. and H.S.), and partially by NIH grants NS048271 and NS095348 (G-l.M.), NS047344, NS097206 and MH106434 (H.S.), MH101454, MH106056, P50AG005138, and AG046170 (K.J.B.), and AI119530 (H.T.).
• Keywords: Cortical neural progenitor; Caspase-3/7; Cyclin-dependent kinase inhibitors; Astrocytes; Drug repurposing screen; High-throughput screening; Zika virus; Microcephaly
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Biology, Virology

Abstract

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 1/46,000 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.