DEVELOPMENT OF ANTIVIRAL THERAPEUTICS FOR COXSACKIEVIRUS TYPE B3 INFECTION
Infekciâ i Immunitet
Enteroviruses are highly diverse group of single-stranded positive RNA viruses belonging to Enterovirus genus from Picornaviridae family. They are the most prevalent viruses in the world. Enteroviruses normally cause seasonal self-limiting infections but they are also known as causative infectious agents of encephalitis, myocarditis, poliomyelitis, acute heart failure and sepsis. Genetic plasticity of enteroviruses allows for widespread epidemics and sporadic outbreaks to occur (for example,
... ur (for example, outbreaks of Enterovirus D68 and Enterovirus 71). Type B Coxsackieviruses of Enterovirus B species is one of commonly identified infectious agents associated predominantly with mild upper respiratory and gastrointestinal illnesses. Nevertheless, Coxsackieviruses B3 infection can result in severe myocarditis leading ultimately to heart failure. The pathogenesis of Coxsackieviruses B3 induced myocarditis is well studied, and it is mediated by both direct injury mediated by viral proteases and indirect damage secondary to host immune responses. There are no approved direct antiviral medications for the treatment of enteroviral infection in particular Coxsackieviruses B3 myocardial infection to date. Neither are there ongoing clinical trials in the field of Coxsackieviruses B3 infection treatment or prophylaxis. Available treatment strategies are mainly supportive to stabilize the patient condition and to relieve discomforts. Possibly, the relatively small market for anti-enteroviral drugs prevents pharma industry from new drug development. The lifecycle of Coxsackieviruses B3 have been extensively studied and attractive targets for drug design are known. The aim of the present review is to describe the current state of the field of antiviral drug design against Coxsackieviruses B3 infection with special focus on direct-acting antivirals, though host factor-targeting inhibitors (including compounds from medicinal plant extracts) are mentioned too. The following categories of direct Coxsackieviruses B3 inhibitors are discussed in details: capsid binders (pleconaril and its derivatives), viral 3C protease inhibitors (rupintrivir and its analogs), drugs, targeting the viral replication (both nucleoside analogs and non-nucleoside inhibitors). Results of drug repurposing screens for amiloride, benzerazide, dibucaine and fluoxetine are also included.