On the Effective Antiviral Treatment of Enterovirus Infections

Enteroviruses (EVs) as causative agents of diseases with varying clinical pictures occupy a significant place in human pathology. The great variability of these approximately 200 viruses is the basis of their comparatively quick development of drug resistance and thus the absence of effective antivirals for clinical use. Monotherapeutic applications of antivirals have been ineffective as anti-enteroviral chemotherapy. Therefore, to overcome the drug resistance barrier, we investigated EV replication inhibitors by looking at the effect of combinations of viral inhibitors in cell culture experiments. The next step was to test anti-EV combinations in vivo, in laboratory animals. The most successful achievement in this study was the development of the consecutive alternating administration (CAA) treatment course of triple combinations of antivirals with different modes of action. The CAA treatment scheme was applied in Coxsackievirus B1 and B3 infections by massive virus inocula (20 MLD50) in suckling albino mice. The CAA treatment scheme was used with three triple combinations, including five specific inhibitors of EV replication: disoxaril, pleconaril, guanidine.HCl, MDL-860 and oxoglaucine. Those experiments demonstrated a pronounced effectivity of the CAA approach expressed with a marked protective effect: decreased mortality and lengthening of the mean survival time. IC50 values (a phenotypic marker) of the virus progeny in virus samples isolated from target organs (brain, heart) of Coxsackievirus B infected mice treated with a triple combination of antivirals via the CAA scheme showed (a) a marked suppression in the development of drug resistance, and (b) in parallel, an unusual phenomenon of an increase in susceptibility to the partner compounds in the combinations. Sequence analysis of the genome (RNA) in samples of target isolates manifested the changes determining the increased susceptibility of the virus to the respective EV inhibitors. The data from these systematic studies show that the CAA treatment scheme with triple combinations of antivirals is an effective chemotherapy for EV infections.