Format

Send to

Choose Destination
Cell Stem Cell. 2017 Aug 3;21(2):274-283.e5. doi: 10.1016/j.stem.2017.06.017. Epub 2017 Jul 20.

High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain.

Author information

1
Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
2
The Center for Stem Cell Biology, New York, NY 10065, USA; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA; Weill-Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA.
3
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
4
Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
5
The Center for Stem Cell Biology, New York, NY 10065, USA; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA.
6
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, 125 Mason Farm Road, Chapel Hill, NC 27599, USA.
7
Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Physiology Biophysics and Systems Biology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
8
The Center for Stem Cell Biology, New York, NY 10065, USA; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA. Electronic address: studerl@mskcc.org.
9
Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu.

Abstract

Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients.

KEYWORDS:

Zika virus; high content chemical screen; human cortical neuron progenitor cells; human forebrain organoids; human pluripotent stem cells

PMID:
28736217
PMCID:
PMC5553280
DOI:
10.1016/j.stem.2017.06.017
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center