On the Effective Antiviral Treatment of Enterovirus Infections

Enteroviruses (EVs) play an important role in human pathology as causative agents of diseases with a wide range of clinical manifestations. The high heterogeneity of these approximately 200 viruses is the cause of their rapid development of drug resistance and, as a result, the lack of appropriate antivirals for clinical use. Antiviral monotherapies have been shown to be ineffective as anti-enteroviral chemotherapy. To overcome the drug resistance barrier, we investigated EV replication inhibitors in cell culture experiments, looking at the impact of combinations of viral inhibitors. Anti-EV combinations were then tested in vivo in laboratory animals. The creation of the consecutive alternating administration (CAA) treatment course of triple combinations of antivirals with different modes of action was the most promising achievement in this research. In suckling albino mice, the CAA treatment scheme was used to treat Coxsackievirus B1 and B3 infections caused by large virus inocula (20 MLD50). The CAA treatment scheme included three triple combinations of five unique EV replication inhibitors: disoxaril, pleconaril, and guanidine. MDL-860, HCl, and oxoglaucine. Those tests revealed that the CAA strategy has a high efficacy, as shown by a significant protective effect: lower mortality and a longer mean survival time. In virus samples isolated from target organs (brain, heart) of Coxsackievirus B infected mice treated with a triple combination of antivirals through the CAA scheme, IC50 values (a phenotypic marker) of the virus progeny showed (a) a marked suppression in the development of drug resistance, and (b) an unusual phenomenon of an increase in susceptibility to the partner compounds in the combi. The changes assessing the virus’s increased resistance to the respective EV inhibitors were revealed by sequencing the genome (RNA) in samples of target isolates. The results of these studies indicate that the CAA treatment scheme, which includes triple antiviral combinations, is an effective chemotherapy for EV infections.

Author (s) Details

Angel S. Galabov
The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.

Adelina Stoyanova
The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.

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