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

• DOI: 10.1016/j.stem.2017.06.017
• Publication Date: 2017-07-20T12:49:06Z
• Authors: Ting Zhou; Lei Tan; Gustav Y. Cederquist; Yujie Fan; Brigham J. Hartley; Suranjit Mukherjee; Mark Tomishima; Kristen J. Brennand; Qisheng Zhang; Robert E. Schwartz; Todd Evans; Lorenz Studer; Shuibing Chen
• Keywords: 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

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.