Comparative analysis of the molecular mechanism of resistance to vapendavir across a panel of picornavirus species

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. ### Competing Interest Statement The authors have declared no competing interest.