New Trends In Development Of Effective Chemotherapy Of Enterovirus Infections
Angel S. Galabov
The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
Abstract: Enteroviruses are causative agents of more than 50 various diseases, among them meningitis, encephalitis, pleurodinia, myocarditis, pericarditis, insulin-dependent diabetes mellitus, uveitis, etc. Each enterovirus induces several clinical syndromes and vice versa, each of these clinical syndrome could be caused by various enteroviruses, a phenomenon unique in the human infectious pathology. Unapparent manifestation or a subclinical course substantially dominates in approximately all enteroviral infections. For this reason a prevailing role in the strategy of countering these infections would have the urgent prophylaxis (i.e. the use of specific anti-enterovirus chemotherapeutic agents administered during disease latency period) of all persons contact to the first clinically manifested cases of infection. The main obstacle of the progress of effective anti-enteroviral chemotherapy is the development of drug-resistance, phenomenon based on the unusually high level of mutation rate (10-3) in the course of enterovirus replication. We carried out systemathic study on the drug-resistance phenomenon in the model of coxsackievirus B neuroinfection in mice treated with disoxaril, a representative of the most efficient anti-enteroviral antivirals, WIN compounds, binding the hydrophobic pocket of VP1 coat protein. In parallel, disoxaril-resistant and disoxaril-dependent mutants have been developed in vitro. Phenotypic characteristics, VP1 genome sequencing and VP1 protein sequence dedication of disoxaril mutants have been determined. Sequence changes gave satisfactory explanation of the drug-resistance and a hypothesis have been formulated on the unusual effect of inhibitor-dependence. Large-scale study on the combination effects of anti-enteroviral agents with different modes of action have been carried out in cell culture experiments and a series of synergistic combinations have been selected. Administration of antivirals in synergistic combinations could be considered as a prospective approach in reducing the level of drug-resistance and in improving the chemotherapeutic efficacy. It was established that the avoiding the drug-resistance development could be attained only by applying a novel approach of consecutive alternating, not simultaneous, administration of the anti-enteroviral substances in combination.
