Discovery of Drug Candidates that Inhibit and Eliminate Zika Virus Infection in Fetal and Adult Brain

Zika virus (ZIKV) infects fetal and adult human brains, and is associated with serious neurological complications including microcephaly and Guillain-Barré Syndrome (GBS). To date, no prophylactic or therapeutic treatment is available to prevent or treat ZIKV infection. Here, we performed a high content chemical screen using a library containing FDA-approved drugs or drug candidates. Two compounds, hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ), were discovered to inhibit ZIKV infection in human cortical neuron progenitor cells (hNPCs). HH was further validated to inhibit ZIKV infection and to rescue ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ suppressed ZIKV infection in adult mouse brain in vivo. Strikingly, HH and AQ fully rescued the severe limb paralysis syndrome developed in ZIKV infected adult mice. This study identifies drug candidates for treatment of ZIKV infection and ZIKV-related neurological complications in fetal and adult patients. Overall design: 6 samples were included as following design: 1) neural progenitor cells (NPCs) with MOCK infection and DMSO treatment, 2) NPCs with MOCK infection and treated with AQ, 2) NPCs with MOCK infection and treated with HH, 4) NPCs infected with ZIKA (MR766 strain) and treated with DMSO, 5) NPCs infected with ZIKA and treated with AQ, 6) NPCs infected with ZIKA and treated with HH. All treatment above was lasted for 3 days.