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

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

  • Antimicrob Agents Chemother. 2016 Apr 22;60(5):2627-38. doi: 10.1128/AAC.02182-15.
Rachel Ulferts 1,  S Matthijn de Boer 1,  Lonneke van der Linden 2,  Lisa Bauer 1,  Hey Rhyoung Lyoo 1,  Maria J Maté 3,  Julie Lichière 3,  Bruno Canard 3,  Daphne Lelieveld 4,  Wienand Omta 4,  David Egan 4,  Bruno Coutard 3,  Frank J M van Kuppeveld 5
Affiliations

Affiliations

  • 1 Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
  • 2 Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
  • 3 CNRS, AFMB UMR 7257, Marseille, France Aix-Marseille Université, CNRS, AFMB UMR 7257, Marseille, France.
  • 4 Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
  • 5 Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands F.J.M.vanKuppeveld@uu.nl.
PMID: 26856848 DOI: 10.1128/AAC.02182-15
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.

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