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.

Novel activities of safe-in-human broad-spectrum antiviral agents

“…We also confirmed previously reported activities of chloroquine against CHIKV and ZIKV, mycophenolic acid against CHIKV and RRV, fluoxetine, pirlindole and dibucaine against EV1, BCX4430, lopinavir and hydroxichloroquine against ZIKV, as well as gemcitabine against EV1, FLUAV, ZIKV and HSV-1 (Cao et al, 2017;Delogu and de Lamballerie, 2011;Delvecchio et al, 2016;Denisova et al, 2012;Julander et al, 2017;Kang et al, 2015;Khan et al, 2011;Kuivanen et al, 2017;Lee et al, 2017;Soderholm et al, 2016;Ulferts et al, 2016;Yuan et al, 2017) (Fig. 4).…”

Direct-acting antivirals and host-targeting strategies to combat enterovirus infections

“…Several structurally disparate 2C ATPase inhibitors have been identified, such as guanidine hydrochloride, HBB, MRL-1237 and TBZE-029 [3]. In addition, drug repurposing screens have recently uncovered a number of FDA-approved drugs (fluoxetine, pirlindole, dibucaine, zuclopenthixol) that inhibit replication of enterovirus species B and D members [39][40][41].…”

Energy Based Pharmacophore Modelling and Docking Studies for Determining Potent Inhibitor Against M2 Proton Channel of Influenza Virus

“…Intriguingly, diphenylmethane and its derivatives are active against a host of viral infections like Bovine-viral diarrhoea virus, A-PR8 virus, poliomyelitis virus, adenovirus, vaccinia virus and MHV3 virus. 56,68 Overall, the results from our analysis along with available experimental evidences comprehend that these 9 lead molecules could be used as promising candidate for M2 protein inhibition. …”

“…In a study conducted in Utrecht University, Netherlands this drug was effective against all enterovirus and rhinoviruses tested. 56 It is a known fact that enteroviruses are positive-sense singlestranded RNA viruses like the retroviruses. As previously mentioned the evolutionary link between positive and negative strand RNA viruses suggests the use of these "hit" molecules for inhibition of influenza virus.…”