High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain
0301 basic medicine
0303 health sciences
Adolescent
Zika Virus Infection
Induced Pluripotent Stem Cells
Drug Evaluation, Preclinical
Amodiaquine
Brain
Mice, SCID
Zika Virus
Antiviral Agents
Cell Line
3. Good health
Organoids
03 medical and health sciences
Fetus
Neural Stem Cells
Amaryllidaceae Alkaloids
Animals
Humans
Female
Child
DOI:
10.1016/j.stem.2017.06.017
Publication Date:
2017-07-20T12:49:06Z
AUTHORS (13)
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.
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