Enteroviruses and Perspectives for Etiotropic Therapy of Enteroviral Infections

Millions of people, mostly children, are infected annually by enteroviruses with a wide variety of clinical manifestations. Most enteroviral infections are inapparent (Modlin et al., 2001), i.e. these viruses circulate in the human population without being “spotted”. In a number of cases they cause clinically manifested illnesses of varying severity, including diseases affecting the central nervous system, heart, endocrine pancreas, etc. The high morbidity, the mortality rates in children and the high-risk groups (immunocompromised patients and newborns), as well as the lack of effective vaccines (excluding polioviruses) determine chemotherapy as the primary means of control of enteroviral infections. Up to now, no effective chemotherapeutic agents for specific treatment of such infections have been registered. A multitude of compounds have been tested, but only few of them are active in vivo. The substances that have reached clinical trial stages have adverse side effects, low selectivity, high toxicity or unfavorable pharmacokinetic properties, and are, therefore, not suitable for use in clinical practice. The main reason for the failure of the anti-enteroviral therapy is that enteroviruses become drug-resistant and even drug-dependent. This is due to the extremely high levels of mutation and recombination in these viruses, leading to heterogeneous mutant populations. One way to combat resistance is to develop approaches for combined application of new or already existing substances with different mechanisms of action. Our team was the first to introduce analysis of the combined effects of selective inhibitors of enterovirus replication with different mechanisms of action (Nikolaeva and Galabov, 1999, 2000, 2011). Furthermore, the process of development of resistance to the most effective enterovirus inhibitors – the WIN compounds – was studied. A panel of phenotype markers was also presented for characterization of drug-dependent mutants (Nikolova and Galabov, 2003; Nikolova et. al., 2011). In addition, a new highly effective approach has been developed for combined administration of anti-enteroviral substances for chemotherapy of coxsackievirus neuroinfection in newborn mice, which could serve as the basis for new therapeutic strategies. It consists in consecutive, alternating, not concomitant, application of the compounds in the combination (consecutive alternating administration treatment course, CAA course). Double, triple and quadruple regimens with some of the best studied anti-enteroviral inhibitors were tested. The highest activity was manifested by the triple combinations in consecutive administration of inhibitors with different mechanisms of action, applied in a strict order (Vassileva-Pencheva and Galabov, 2010; Stoyanova et.al., 2015).