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Nat Med. 2016 Oct;22(10):1101-1107. doi: 10.1038/nm.4184. Epub 2016 Aug 29.

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

Author information

1
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
2
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
3
Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
4
Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, Georgia, USA.
5
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA.
6
Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
7
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
8
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
9
Biomedical Engineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
10
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
11
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
12
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
13
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
14
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
15
The Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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.

PMID:
27571349
PMCID:
PMC5386783
DOI:
10.1038/nm.4184
[Indexed for MEDLINE]
Free PMC Article

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