Key result
Consecutive alternating administration of pleconaril, MDL-860, and oxoglaucine induced specific viral genome mutations that prevented drug resistance and increased drug susceptibility in CVB1-infected mice.
Why the study?
To clarify the genetic basis of the absence of drug resistance and increased antiviral susceptibility observed during consecutive alternating administration of enterovirus inhibitors in CVB1-infected mice.
Does consecutive alternating administration of pleconaril/MDL-860/oxoglaucine alter viral genome mutations to prevent drug resistance in CVB1-infected newborn mice?
Does consecutive alternating administration of pleconaril/MDL-860/oxoglaucine alter viral genome mutations to prevent drug resistance in CVB1-infected newborn mice?
Consecutive alternating administration of enterovirus inhibitors induces specific viral genome changes that may prevent drug resistance and increase susceptibility.
Background We developed a new approach for the treatment of enterovirus infections, the consecutive alternating administration (CAA) of a combination of enterovirus inhibitors. On the model of coxsackievirus B1 (CVB1) in mice, two phenomena were observed: absence of drug resistance and increased susceptibility to the antivirals. This study aims to clarify the genetic basis of these phenomena. Methods Brain samples from CVB1-infected mice subjected to a CAA course with the combination pleconaril/MDL-860/oxoglaucine were used for viral RNA extraction and next generation sequencing. In parallel, samples from monotherapeutic courses of the three substances included in the combination were studied. Whole genome sequence analysis was carried out on all samples. Results Samples of pleconaril monotherapy showed mutations in 5′untranslated region, VP3, 2C, 3C and 2A regions of viral RNA, translated in amino acid substitution of the 2A protein. The MDL-860 course induced changes in CVB1 RNA in the VP3 and 2C regions. The oxoglaucine monotherapy samples showed RNA mutation and amino acid substitution in the VP1 region and nucleotide substitution in the 3D region. In the specimens taken from mice subjected to the CAA course with pleconaril/MDL-860/oxoglaucine, the following RNA mutations were established: 5′ untranslated region, 2A, and 2B, and amino acids substitutions in VP3 and 2A, which differ from those mentioned above. These changes could be the reason for the prevention of drug resistance development and also to be considered as the basis for the phenomenon of increased drug susceptibility. Conclusions The results reveal that the high anti-enteroviral efficacy of the CAA course is substantiated by the appearance of specific changes in the viral genome.
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Grozdanov et al. (2020) studied Coxsackievirus B1 infection. Consecutive alternating administration of pleconaril, MDL-860, and oxoglaucine vs. Placebo and monotherapies was evaluated on Viral genome mutations (nucleotide and amino acid substitutions). Consecutive alternating administration of pleconaril, MDL-860, and oxoglaucine induced specific viral genome mutations that prevented drug resistance and increased drug susceptibility in CVB1-infected mice.
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