Screening of a Library of FDA-Approved Drugs Identifies Several Enterovirus Replication Inhibitors That Target Viral Protein 2C

Rachel Ulferts, S Matthijn de Boer, Lonneke van der Linden, Lisa Bauer, Hey Rhyoung Lyoo, Maria J Maté, Julie Lichière, Bruno Canard, Daphne Lelieveld, Wienand Omta, David Egan, Bruno Coutard, Frank J M van Kuppeveld

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Enteroviruses (EVs) represent many important pathogens of humans. Unfortunately, no antiviral compounds currently exist to treat infections with these viruses. We screened the Prestwick Chemical Library, a library of approved drugs, for inhibitors of coxsackievirus B3, identified pirlindole as a potent novel inhibitor, and confirmed the inhibitory action of dibucaine, zuclopenthixol, fluoxetine, and formoterol. Upon testing of viruses of several EV species, we found that dibucaine and pirlindole inhibited EV-B and EV-D and that dibucaine also inhibited EV-A, but none of them inhibited EV-C or rhinoviruses (RVs). In contrast, formoterol inhibited all enteroviruses and rhinoviruses tested. All compounds acted through the inhibition of genome replication. Mutations in the coding sequence of the coxsackievirus B3 (CV-B3) 2C protein conferred resistance to dibucaine, pirlindole, and zuclopenthixol but not formoterol, suggesting that 2C is the target for this set of compounds. Importantly, dibucaine bound to CV-B3 protein 2C in vitro, whereas binding to a 2C protein carrying the resistance mutations was reduced, providing an explanation for how resistance is acquired.

Original languageEnglish
Pages (from-to)2627-2638
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number5
DOIs
Publication statusPublished - 2016

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