Key result
In vitro selection of vapendavir-resistant picornaviruses identified mutations both inside and outside the drug-binding pocket of VP1, with one mutation (G149C in hRV2) making viral replication dependent on the drug.
Vapendavir resistance in picornaviruses involves complex mechanisms including mutations outside the drug-binding pocket that can lead to drug-dependent viral replication.
Outside-pocket mutations may confer vapendavir resistance; leaves open expanded surveillance for capsid-inhibitor escape.
Vapendavir is a rhino/enterovirus inhibitor that targets a hydrophobic pocket in the viral capsid. Drug-resistant variants were selected in vitro . Mutations in the drug-binding pocket in VP1 (C199R/Y in hRV14; I194F in PV1; M252L and A156T in EV-D68), typical for this class of compounds, were identified. We also observed mutations that are located outside the pocket (K167E in EV-D68 and G149C in hRV2) and that contribute to the resistant phenotype. Remarkably, the G149C substitution made the replication of human rhinovirus 2 dependent on the presence of vapendavir. Our data suggest that vapendavir binding to the capsid of the dependent isolate may be required to stabilize the viral particle and to allow efficient dissemination of the virus. Our results demonstrate that vapendavir-resistant pheno- and genotypes of clinically relevant picornavirus species are more complex than generally believed.
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Lanko et al. (2020) studied Picornavirus infection (in vitro). Vapendavir vs. Wild-type virus was evaluated on Antiviral activity (EC50) and resistance mutations. In vitro selection of vapendavir-resistant picornaviruses identified mutations both inside and outside the drug-binding pocket of VP1, with one mutation (G149C in hRV2) making viral replication dependent on the drug.
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