1. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen
- Author
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Hengli Tang, Jennifer Kouznetsova, Paul Shinn, Wei Zheng, Wei Kai Huang, Menghang Xia, Miao Xu, Christy Hammack, Julia Tcw, Chase Allen, Xuyu Qian, Alison Goate, Ha Nam Nguyen, Zhexing Wen, Wenwei Huang, Guo Li Ming, Hongjun Song, Samuel G. Michael, Kristen J. Brennand, Sarah C. Ogden, Ruili Huang, Anton Simeonov, Yichen Cheng, Catherine Hanna, Kimberly M. Christian, Fadi Jacob, Misha Itkin, and Emily M. Lee
- Subjects
0301 basic medicine ,Drug ,Programmed cell death ,media_common.quotation_subject ,Induced Pluripotent Stem Cells ,Pharmacology ,Virus Replication ,General Biochemistry, Genetics and Molecular Biology ,Article ,Zika virus ,Cell Line ,03 medical and health sciences ,Neural Stem Cells ,medicine ,Humans ,Pentanoic Acids ,Niclosamide ,media_common ,Neurons ,biology ,Cell Death ,Kinase ,Caspase 3 ,Zika Virus Infection ,Drug Repositioning ,Brain ,General Medicine ,Zika Virus ,biology.organism_classification ,Virology ,Caspase Inhibitors ,Organoids ,Drug repositioning ,030104 developmental biology ,Drug development ,Cell culture ,Astrocytes ,Microcephaly ,medicine.drug - 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 ∼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.
- Published
- 2016