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Viruses ; 14(1)2022 01 08.
Article in English | MEDLINE | ID: mdl-35062313

ABSTRACT

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs as of yet to treat EV71 infections. In this study, we conducted antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug's antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be greatly relieved by exposing virus-infected cells to extracellular low-pH culture media. Ultimately, we have identified a use for an FDA-approved antidepressant in broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.


Subject(s)
Antidepressive Agents/pharmacology , Antiviral Agents/pharmacology , Enterovirus Infections/drug therapy , Enterovirus/drug effects , Sertraline/pharmacology , Virus Internalization/drug effects , Antidepressive Agents/therapeutic use , Cell Line , Cell Survival , Drug Evaluation, Preclinical , Enterovirus Infections/virology , Hand, Foot and Mouth Disease/drug therapy , HeLa Cells , Humans , Hydrogen-Ion Concentration , Sertraline/therapeutic use , Virus Replication/drug effects
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