title: Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.
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.
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.|Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Miao
authors: M
authors: Xu
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Emily M
authors: EM
authors: Lee
authors: Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, Georgia, USA.|Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA.|Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.|Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Zhexing
authors: Z
authors: Wen
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Yichen
authors: Y
authors: Cheng
authors: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Wei-Kai
authors: WK
authors: Huang
authors: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Biomedical Engineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Xuyu
authors: X
authors: Qian
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors: Julia
authors: J
authors: Tcw
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Jennifer
authors: J
authors: Kouznetsova
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Sarah C
authors: SC
authors: Ogden
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Christy
authors: C
authors: Hammack
authors: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Fadi
authors: F
authors: Jacob
authors: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Ha Nam
authors: HN
authors: Nguyen
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Misha
authors: M
authors: Itkin
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Catherine
authors: C
authors: Hanna
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Paul
authors: P
authors: Shinn
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Chase
authors: C
authors: Allen
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Samuel G
authors: SG
authors: Michael
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Anton
authors: A
authors: Simeonov
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Wenwei
authors: W
authors: Huang
authors: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Kimberly M
authors: KM
authors: Christian
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors: Alison
authors: A
authors: Goate
authors: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors: Kristen J
authors: KJ
authors: Brennand
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Ruili
authors: R
authors: Huang
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Menghang
authors: M
authors: Xia
authors: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Biomedical Engineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|The Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Guo-Li
authors: GL
authors: Ming
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors: Wei
authors: W
authors: Zheng
authors: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Biomedical Engineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|The Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Hongjun
authors: H
authors: Song
authors: Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
authors: Hengli
authors: H
authors: Tang
mesh_terms: D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D058492:Drug Repositioning; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects; D008831:Microcephaly / Q000517:prevention & control; D058953:Neural Stem Cells / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009534:Niclosamide / Q000494:pharmacology*; D009940:Organoids; D010421:Pentanoic Acids / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects*; D000071243:Zika Virus Infection / Q000188:drug therapy*
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D010421:Pentanoic Acids; D009534:Niclosamide; D053148:Caspase 3