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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Amaryllidaceae Alkaloids / pharmacology
  • Amodiaquine / pharmacology
  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Brain / virology*
  • Cell Line
  • Child
  • Drug Evaluation, Preclinical / methods*
  • Female
  • Fetus / drug effects
  • Fetus / virology
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism*
  • Mice, SCID
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism*
  • Organoids / drug effects
  • Organoids / virology*
  • Zika Virus / drug effects
  • Zika Virus / physiology*
  • Zika Virus Infection / drug therapy*
  • Zika Virus Infection / pathology

Substances

  • Amaryllidaceae Alkaloids
  • Antiviral Agents
  • Amodiaquine
  • hippeastrine