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
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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