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Perspectives for effective chemotherapy of enterovirus infections

Abstract : Human enteroviruses distributed worldwide are causative agents of a broad spectrum of diseases with extremely high morbidity, including a series of severe illnesses of the central nervous system, heart, endocrine pancreas, skeleton muscles, etc., as well as the common cold contributing to the development of chronic respiratory diseases, and the chronic obstructive pulmonary disease. The above diseases along with significantly high morbidity and mortality in children, in the high-risk populations (immunodeficiencies, neonates) definitely formulate the chemotherapy as the main tool for the control of enterovirus infections. At present, clinically effective antivirals for use in the treatment of enteroviral infection do not exist, in spite of the lots of work carried out in this field. The main reason for this is the development of drug resistance. The monotherapy courses were the only approach used till now. For the first time in the research for anti-enterovirus antivirals our team introduced the testing of combination effect of the selective inhibitors of enterovirus replication with different mode of action. We studied alongside the process of development of resistance to the strongest inhibitors of enteroviruses, WIN compounds (VP1 protein hydrophobic pocket blockers), especially in the models in vivo, CVB infections in mice. We introduced the tracing of a panel of phenotypic markers (MIC50 value, plaque shape and size, stability at 50o C, pathogenicity in mice) for characterization the drug-mutants (resistant and dependent) as a very important stage in the study of enterovirus inhibitors. Moreover, as a result of VP1 RNA sequence analysis performed on the model of disoxaril mutants of CVB1, we determined the molecular basis of the drug-resistance, two point mutations - M213H and F237L, both in the ligand-binding pocket. The sequence analysis of the drug-dependent mutant showed some reversion to the wild drug-sensitive virus strain. A large-scale study of the combined effect of a series of anti-enteroviral agents with different modes of action resulted in the selection of a number of very effective in vitro double combinations revealing synergistic character of the combination effect and a broad spectrum of sensitive enteroviruses. Two antivirals developed in our previous studies were involved in these studies, PTU-23 and oxoglaucine. The most prospective attainment in our study in this field was the development of a novel scheme for the combined application of anti-enteroviral substances in coxsackievirus B1 neuroinfection in newborn mice. It consisted of a consecutive, alternating and non-simultaneous, administration of the substances in the combination. A triple combination - disoxaril-guanidine.HCl-oxoglaucine (DGO), showing good efficacy was selected. Its effectiveness was expressed in a marked reduction of mortality rate in infected mice as compared both to the placebo group, and to the partner compounds used alone every day, and to the same combination applied simultaneously every day. Studies of the drug sensitivity of viral brain isolates from mice, treated with DGO combination showed not only preserved, but even increased sensitivity to the drugs included in the combination. Obviously, the consecutive alternating administration of anti-enteroviral substances hinders the occurrence of drug-resistance in the course of the experimental enteroviral infections in mice.
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https://hal-riip.archives-ouvertes.fr/pasteur-00708578
Contributor : Ivanka Nikolova <>
Submitted on : Friday, June 15, 2012 - 1:02:05 PM
Last modification on : Monday, October 8, 2018 - 5:44:06 PM
Long-term archiving on: : Sunday, September 16, 2012 - 2:45:36 AM

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Angel S Galabov, Nikolaeva-Glomb Lubomira, Ivanka Nikolova, Pencheva Ralitza V. Perspectives for effective chemotherapy of enterovirus infections. New Trends in Microbiology, 2012, 1 (1), p. 47-81. ⟨pasteur-00708578⟩

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