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

TitleHigh-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain.
Publication TypeJournal Article
Year of Publication2017
AuthorsZhou T, Tan L, Cederquist GY, Fan Y, Hartley BJ, Mukherjee S, Tomishima M, Brennand KJ, Zhang Q, Schwartz RE, Evans T, Studer L, Chen S
JournalCell Stem Cell
Volume21
Issue2
Pagination274-283.e5
Date Published2017 08 03
ISSN1875-9777
KeywordsAdolescent, Amaryllidaceae Alkaloids, Amodiaquine, Animals, Antiviral Agents, Brain, Cell Line, Child, Drug Evaluation, Preclinical, Female, Fetus, Humans, Induced Pluripotent Stem Cells, Mice, SCID, Neural Stem Cells, Organoids, Zika Virus, Zika Virus Infection
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.

DOI10.1016/j.stem.2017.06.017
Alternate JournalCell Stem Cell
PubMed ID28736217
PubMed Central IDPMC5553280
Grant ListDP3 DK111907 / DK / NIDDK NIH HHS / United States
F30 MH113343 / MH / NIMH NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
DP2 DK098093 / DK / NIDDK NIH HHS / United States
R21 AI117213 / AI / NIAID NIH HHS / United States
R01 MH106056 / MH / NIMH NIH HHS / United States
R01 MH101454 / MH / NIMH NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
K08 DK101754 / DK / NIDDK NIH HHS / United States

Person Type: