Development of resistance to disoxaril in Coxsackie B1 virus-infected newborn mice.

Treatment with disoxaril (a WIN compound binding to the hydrophobic pocket within the enterovirus VP1 capsid protein) in newborn mice infected with Coxsackie B1 virus, for 10 days post virus inoculation at a daily subcutaneous dose of 25mg/kg decreased the virus titer in the mouse brain till day 7. Thereafter (on days 8 and 9) drug-resistant virus progeny in brain samples isolates was noted with disoxaril IC(50) values of >40 microM as compared to 0.59-1.37 microM in placebo. Study on phenotypic characteristics of the disoxaril-resistant mutants (as obtained in vivo or in cell culture experiments in parallel with the wild disoxaril-sensitive virus) showed: (i) larger size of virus plaques under agar overlay; (ii) more irregular shape of virus plaques; (iii) markedly less thermostability at 50 degrees C; (iv) slightly increased pathogenicity for newborn mice. The results obtained provide convincing evidence for the development of drug-resistant progeny of Coxsackie B1 virus in the brain of mice following treatment with disoxaril.