Tuesday, 1 August 2017

Plant-Derived Drug Shows Powerful Ability to Eliminate Zika Virus Infection from Brain Cells SHORT ARTICLESwitch to Standard View High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain Ting Zhou11, Lei Tan11, Gustav Y. Cederquist11, Yujie Fan, Brigham J. Hartley, Suranjit Mukherjee, Mark Tomishima, Kristen J. Brennand, Qisheng Zhang, Robert E. Schwartz, Todd Evans, Lorenz Studer'Correspondence information about the author Lorenz StuderEmail the author Lorenz Studer, Shuibing Chen12,'Correspondence information about the author Shuibing ChenEmail the author Shuibing Chen 11These authors contributed equally 12Lead Contact Publication stage: In Press Corrected Proof DOI: showArticle Info Summary Full Text Methods Images/Data References Related Articles Comments Graphical Abstract Figure thumbnail fx1 Highlights •A screen with >1,000 FDA-approved drug candidates finds anti-ZIKV compounds in hNPCs •Hippeastrine hydrobromide eliminates virus from hNPCs infected with ZIKV •Hippeastrine hydrobromide inhibits ZIKV infection in fetal-like forebrain organoids •Hippeastrine hydrobromide suppresses ZIKV in mice carrying infectious virus Summary 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: high content chemical screen, human pluripotent stem cells, human cortical neuron progenitor cells, human forebrain organoids, Zika virus

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