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.

中文翻译：

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hPSC 神经祖细胞的高内涵筛选鉴定出可抑制胎儿类器官和成人大脑中寨卡病毒感染的候选药物。

寨卡病毒 (ZIKV) 感染胎儿和成人的大脑，并与严重的神经系统并发症有关。迄今为止，尚无可用于治疗 ZIKV 感染患者的治疗方法。我们使用人多能干细胞来源的皮质神经祖细胞（hNPC）进行了高内涵化学筛选，发现氢溴酸马匹斯汀（HH）和二水合阿莫地喹（AQ）可以抑制hNPC中的ZIKV感染。进一步验证表明，HH 还可以挽救 ZIKV 诱导的 hNPC 和人类胎儿样前脑类器官的生长和分化缺陷。最后，HH 和 AQ 在体内抑制成年小鼠大脑中的 ZIKV 感染。引人注目的是，当对感染 ZIKV 的成年小鼠施用 HH 时，HH 可以抑制病毒传播，凸显了其治疗潜力。我们的方法强调了基于干细胞的筛选和在人类前脑类器官和小鼠模型中的验证在识别治疗胎儿和成人患者 ZIKV 感染和相关神经系统并发症的候选药物方面的力量。