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

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

doi:10.1016/j.stem.2017.06.017

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

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

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195 Scopus citations

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.

Original language	English
Pages (from-to)	274-283.e5
Journal	Cell Stem Cell
Volume	21
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2017.06.017
State	Published - 3 Aug 2017

Keywords

Zika virus
high content chemical screen
human cortical neuron progenitor cells
human forebrain organoids
human pluripotent stem cells

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10.1016/j.stem.2017.06.017

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Zhou, T., Tan, L., Cederquist, G. Y., Fan, Y., Hartley, B. J., Mukherjee, S., Tomishima, M., Brennand, K. J., Zhang, Q., Schwartz, R. E., Evans, T., Studer, L., & Chen, S. (2017). 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, 21(2), 274-283.e5. https://doi.org/10.1016/j.stem.2017.06.017

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

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",

author = "Ting Zhou and Lei Tan and Cederquist, {Gustav Y.} and Yujie Fan and Hartley, {Brigham J.} and Suranjit Mukherjee and Mark Tomishima and Brennand, {Kristen J.} and Qisheng Zhang and Schwartz, {Robert E.} and Todd Evans and Lorenz Studer and Shuibing Chen",

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year = "2017",

month = aug,

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doi = "10.1016/j.stem.2017.06.017",

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Zhou, 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 2017, '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, vol. 21, no. 2, pp. 274-283.e5. https://doi.org/10.1016/j.stem.2017.06.017

TY - JOUR

T1 - High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain

AU - Zhou, Ting

AU - Tan, Lei

AU - Cederquist, Gustav Y.

AU - Fan, Yujie

AU - Hartley, Brigham J.

AU - Mukherjee, Suranjit

AU - Tomishima, Mark

AU - Brennand, Kristen J.

AU - Zhang, Qisheng

AU - Schwartz, Robert E.

AU - Evans, Todd

AU - Studer, Lorenz

AU - Chen, Shuibing

PY - 2017/8/3

Y1 - 2017/8/3

N2 - 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.

AB - 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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KW - high content chemical screen

KW - human cortical neuron progenitor cells

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IS - 2

ER -

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

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