Screening of Natural Extracts for Inhibitors against Japanese Encephalitis Virus Infection

Guo, Jiao; Jia, Xiaoying; Liu, Yang; Wang, Shaobo; Cao, Junyuan; Zhang, Bo; Xiao, Gengfu; Wang, Wei

The top two compounds, FDA-approved Na Ï© /K Ï© -ATPase inhibitors ouabain and digoxin, are cardiac glycosides with similar chemical structures and have been used for the treatment of cardiac arrhythmias and hypotension for more than 200 years. Recently, ouabain and digoxin have been proven to inhibit different kinds of viruses, including enveloped viruses such as coronaviruses, nonenveloped viruses such as reoviruses, DNA viruses such as human cytomegalovirus, positive-sense RNA viruses such as chikungunya virus, and negative-sense RNA viruses such as lymphocytic choriomeningitis virus (LCMV) (21) (22) (23) (24) (25) . Notably, we have tried to select drug-resistant variants by serial passaging of JEV using increasing concentrations of digoxin and ouabain, respectively. However, no adaptive mutant was found after 25 passages with either drug. This result suggested that both drugs might exert the antiviral effects by targeting the cellular protein other than the viral protein, making the barrier to resistance more difficult to overcome.