Key result
V-073, a poliovirus capsid inhibitor, suppressed the emergence of drug-resistant variants in infected mice and cell cultures by forming chimeric capsids that render drug-susceptible genomes dominant.
Why the study?
Does targeting dominant drug targets suppress the emergence of antiviral resistance in poliovirus-infected mice and cells?
Does targeting dominant drug targets suppress the emergence of antiviral resistance in poliovirus-infected mice and cells?
Targeting dominant drug targets, such as oligomeric capsid proteins, can suppress the emergence of antiviral resistance by rendering drug-susceptible genomes dominant.
May guide dominant-target antiviral design; leaves open translation from mouse models to human resistance suppression.
The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a 'dominant drug target' suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu.
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Tanner et al. (2014) studied Poliovirus infection. V-073 vs. Guanidine or untreated controls was evaluated on Emergence of drug-resistant viral variants. V-073, a poliovirus capsid inhibitor, suppressed the emergence of drug-resistant variants in infected mice and cell cultures by forming chimeric capsids that render drug-susceptible genomes dominant.
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