RT Journal Article
SR Electronic
T1 Development and validation of a phenotypic high-content imaging assay for assessing the antiviral activity of small-molecule inhibitors targeting the Zika virus
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 302927
DO 10.1101/302927
A1 Jean A. Bernatchez
A1 Zunhua Yang
A1 Michael Coste
A1 Jerry Li
A1 Sungjun Beck
A1 Yan Liu
A1 Alex E. Clark
A1 Zhe Zhu
A1 Lucas A. Luna
A1 Christal D. Sohl
A1 Byron W. Purse
A1 Rongshi Li
A1 Jair L. de Siqueira-Neto
YR 2018
UL http://biorxiv.org/content/early/2018/04/17/302927.abstract
AB Zika virus (ZIKV) has been linked to the development of microcephaly in newborns, as well as Guillain-Barré syndrome. There are currently no drugs available to treat infection, and accordingly there is an unmet medical need for discovery of new therapies. High-throughput drug screening efforts focusing on indirect readouts of cell viability are prone to a higher frequency of false positives in cases where the virus is viable in the cell but the cytopathic effect is reduced or delayed. Here, we describe a fast and label-free phenotypic high-content imaging assay used to detect cells affected by the viral-induced cytopathic effect (CPE) using automated imaging and analysis. Protection from CPE correlates with a decrease in viral antigen production as observed by immunofluorescence. We trained our assay using a collection of nucleoside analogues against ZIKV; the previously reported antiviral activities of 2’-C-methylribonucleosides and ribavirin against the Zika virus in Vero cells were confirmed using our developed method. Profiling of a novel library of 24 natural product derivatives using our assay revealed compound 1 as an inhibitor of ZIKV-induced cytopathic effect; activity of the compound was confirmed in human fetal neural stem cells (NSCs). The described technique can be easily leveraged as a primary screening assay for profiling large compound libraries against ZIKV, and can be expanded to other ZIKV strains and other cell lines displaying morphological changes upon ZIKV infection.