Human Enterovirus B: Selective Inhibition by Quinoxaline Derivatives and Bioinformatic RNA-Motif Identification as New Targets

Abstract

The Enterovirus genus includes many viruses that are pathogenic in humans, including Coxsackie viruses and rhinoviruses, as well as the emerging enteroviruses D68 and A71. Currently, effective antiviral agents are not available for the treatment or prevention of enterovirus infections, which remain an important threat to public health. We recently identified a series of quinoxaline derivatives that were provento be potent inhibitors of coxsackievirus B5, the most common and a very important human pathogen belonging to the enterovirus genus. We have shown how most active derivatives interfere with the earliest stages of viral replication, blocking infection. Considering the broad antiviral spectrum, a very attractive property for an antiviral drug, we aimed to investigate the antiviral activity of the most promising compounds against other Enterovirus species. Here, we investigated the susceptibility of a panel of representatives of Enterovirus genus (enterovirus A71, belonging to A species; coxsackieviruses B4 and B3;echovirus 9, belonging to B species; and enterovirus D68, belonging to D species) to quinoxaline inhibitors. We also tested cytotoxicity and selectivity indices of the selected compounds, as well as their effects on virus yield.We also investigated their potential mechanism of action by a time course assay. In addition, a bioinformatic analysis was carried out to discover potential new conserved motifs in CVB3 and CVB4 compared to the other enterovirus species that can be used as new targets.

Direct-Acting Antivirals and Host-Targeting Approaches against Enterovirus B Infections: Recent Advances

“…This CV-selective activity could be partially explained by differences in the VP-1 protein sequences. Moreover, an RNA-binding motif analysis through an RNA-Binding Protein DataBase (RBPDB) aimed at revealing new targets in CVs, revealed that only CV-3 and CV-4 share the binding motif for SRSF13, a serine-arginine rich splicing factor involved in splicing events which might alter viral replication and be a potential innovative target for these compounds [ 18 ].…”

Design, Synthesis, and Antiviral Activities of New Benzotriazole-Based Derivatives

“…Most of the FDA-approved drugs possess the N -heterocycle skeleton [ 28 ], which can be differently functionalized to obtain different compounds endowed with biological properties and, therefore, various pharmacological applications [ 29 ]. A wide number of nitrogen-containing heterocyclic derivatives were recognized to exhibit a broad range of pharmacological effects [ 30 , 31 , 32 , 33 , 34 ] and were widely reported in the literature to show intriguing biological activities for these types of compounds [ 35 , 36 , 37 ].…”