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.
Highlights
IntroductionEnterovirus (EV) is a genus belonging to the large Picornaviridae family, which, at present, includes nine enterovirus species (namely, enterovirus A, B, C, D, E, F, G, H, andJ) and three rhinovirus species (rhinovirus A, B, and C)
Enterovirus (EV) is a genus belonging to the large Picornaviridae family, which, at present, includes nine enterovirus species and three rhinovirus species
Looking at the two thiobenzoic-based derivatives,6 and 7, we can point to a slight improvement when the acidic moiety is freed and not protected as an ethyl ester, while the latter can be considered a poPharmaceuticals 2022, 15, 181 tential future pro-drug with good antiviral activity, which will not be lost after metabolic hydrolyzation of the ester group
Summary
Enterovirus (EV) is a genus belonging to the large Picornaviridae family, which, at present, includes nine enterovirus species (namely, enterovirus A, B, C, D, E, F, G, H, andJ) and three rhinovirus species (rhinovirus A, B, and C). Current taxonomy assignsenteroviruses infecting humans to four species: enterovirus A to enterovirus D [1]. Among these important human pathogens are poliovirus, Coxsackie virus, and rhinovirus, as well as the emerging enterovirus D68 and A71. The most relevant agent in the EV genus is probably the poliovirus, which is considered the prototype of the genus and responsible for acute flaccid paralysis. EV-A71 has been reported as the causative agent of widespread epidemics of hand–foot–mouth disease, herpangina, encephalitis, and acute flaccid paralysis [3]. Species A Coxsackievirus have been associated with flaccid paralysis due to generalized myositis, while group B Coxsackievirus (CVB) have been related to spastic paralysis, owing to important muscle injury and degeneration of neuronal tissue
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