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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\n            <jats:italic>in vitro<\/jats:italic>\n            , whereas binding to a 2C protein carrying the resistance mutations was reduced, providing an explanation for how resistance is acquired.\n          <\/jats:p>","DOI":"10.1128\/aac.02182-15","type":"journal-article","created":{"date-parts":[[2016,2,9]],"date-time":"2016-02-09T04:33:28Z","timestamp":1454992408000},"page":"2627-2638","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":73,"title":["Screening of a Library of FDA-Approved Drugs Identifies Several Enterovirus Replication Inhibitors That Target Viral Protein 2C"],"prefix":"10.1128","volume":"60","author":[{"given":"Rachel","family":"Ulferts","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Matthijn","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lonneke","family":"van der Linden","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hey Rhyoung","family":"Lyoo","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J.","family":"Mat\u00e9","sequence":"additional","affiliation":[{"name":"CNRS, AFMB UMR 7257, Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, CNRS, AFMB UMR 7257, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Lichi\u00e8re","sequence":"additional","affiliation":[{"name":"CNRS, AFMB UMR 7257, Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, CNRS, AFMB UMR 7257, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Canard","sequence":"additional","affiliation":[{"name":"CNRS, AFMB UMR 7257, Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, CNRS, AFMB UMR 7257, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"Lelieveld","sequence":"additional","affiliation":[{"name":"Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wienand","family":"Omta","sequence":"additional","affiliation":[{"name":"Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Egan","sequence":"additional","affiliation":[{"name":"Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Coutard","sequence":"additional","affiliation":[{"name":"CNRS, AFMB UMR 7257, Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, CNRS, AFMB UMR 7257, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J. 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