title: Screening of a Library of FDA-Approved Drugs Identifies Several Enterovirus Replication Inhibitors That Target Viral Protein 2C.
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.
authors: Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: Rachel
authors: R
authors: Ulferts
authors: Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: S Matthijn
authors: SM
authors: de Boer
authors: Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
authors: Lonneke
authors: L
authors: van der Linden
authors: Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: Lisa
authors: L
authors: Bauer
authors: Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: Hey Rhyoung
authors: HR
authors: Lyoo
authors: CNRS, AFMB UMR 7257, Marseille, France Aix-Marseille Université, CNRS, AFMB UMR 7257, Marseille, France.
authors: Maria J
authors: MJ
authors: Maté
authors: CNRS, AFMB UMR 7257, Marseille, France Aix-Marseille Université, CNRS, AFMB UMR 7257, Marseille, France.
authors: Julie
authors: J
authors: Lichière
authors: CNRS, AFMB UMR 7257, Marseille, France Aix-Marseille Université, CNRS, AFMB UMR 7257, Marseille, France.
authors: Bruno
authors: B
authors: Canard
authors: Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors: Daphne
authors: D
authors: Lelieveld
authors: Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors: Wienand
authors: W
authors: Omta
authors: Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors: David
authors: D
authors: Egan
authors: CNRS, AFMB UMR 7257, Marseille, France Aix-Marseille Université, CNRS, AFMB UMR 7257, Marseille, France.
authors: Bruno
authors: B
authors: Coutard
authors: Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands F.J.M.vanKuppeveld@uu.nl.
authors: Frank J M
authors: FJ
authors: van Kuppeveld
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics; D003006:Clopenthixol / Q000494:pharmacology; D003992:Dibucaine / Q000494:pharmacology; D004770:Enterovirus / Q000187:drug effects* / Q000235:genetics; D005473:Fluoxetine / Q000494:pharmacology; D000068759:Formoterol Fumarate / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D012229:Rhinovirus / Q000187:drug effects / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D002227:Carbazoles; D002352:Carrier Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D005473:Fluoxetine; D003006:Clopenthixol; C076023:2C protein, viral; D003992:Dibucaine; C009830:pirlindole; D000068759:Formoterol Fumarate