title: Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library.
abstract: BackgroundThe recent epidemics of Zika virus (ZIKV) implicated it as the cause of serious and potentially lethal congenital conditions such microcephaly and other central nervous system defects, as well as the development of the Guillain-Barré syndrome in otherwise healthy patients. Recent findings showed that anti-Dengue antibodies are capable of amplifying ZIKV infection by a mechanism similar to antibody-dependent enhancement, increasing the severity of the disease. This scenario becomes potentially catastrophic when the global burden of Dengue and the advent of the newly approved anti-Dengue vaccines in the near future are taken into account. Thus, antiviral chemotherapy should be pursued as a priority strategy to control the spread of the virus and prevent the complications associated with Zika.MethodsHere we describe a fast and reliable cell-based, high-content screening assay for discovery of anti-ZIKV compounds. This methodology has been used to screen the National Institute of Health Clinical Collection compound library, a small collection of FDA-approved drugs.Results and conclusionFrom 725 FDA-approved compounds triaged, 29 (4%) were found to have anti-Zika virus activity, of which 22 had confirmed (76% of confirmation) by dose-response curves. Five candidates presented selective activity against ZIKV infection and replication in a human cell line. These hits have abroad spectrum of chemotypes and therapeutic uses, offering valuable opportunities for selection of leads for antiviral drug discovery.
authors.affiliation: Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas-SP, 10000, Brazil; Present Address: Instituto Butantan, São Paulo-SP, 1500, Brazil.
authors.forename: Bruno S
authors.initials: BS
authors.lastname: Pascoalino
authors.affiliation: BIOASTER, Paris, 75015, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Courtemanche
authors.affiliation: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz -Fiocruz, Recife/PE, Brazil.
authors.forename: Marli T
authors.initials: MT
authors.lastname: Cordeiro
authors.affiliation: Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz -Fiocruz, Recife/PE, Brazil.
authors.forename: Laura H V G
authors.initials: LH
authors.lastname: Gil
authors.affiliation: Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas-SP, 10000, Brazil; Present Address: Instituto Butantan, São Paulo-SP, 1500, Brazil.
authors.forename: Lucio
authors.initials: L
authors.lastname: Freitas-Junior
keywords: FDA-approved drugs; High content screening drug discovery; Zika