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

Abstract

Vapendavir is a rhino/enterovirus inhibitor that targets a hydrophobic pocket in the viral capsid preventing the virus from entering the cell. We set out to study and compare the molecular mechanisms of resistance to vapendavir among clinically relevant Picornavirus species. To this end in vitro resistance selection of drug-resistant isolates was applied in rhinovirus 2 and 14, enterovirus-D68 and Poliovirus 1 Sabin. 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. Interestingly, we also observed mutations located outside the pocket (K167E in EV-D68 and G149C in hRV2) that contribute to the resistant phenotype. Remarkably, the G149C substitution rendered the replication of human rhinovirus 2 dependent on the presence of vapendavir. Our data suggest that the binding of vapendavir to the capsid of the G149C isolate may be required to stabilize the viral particle and to allow efficient dissemination of the virus. We observed the dependency of the G149C isolate on other compounds of this class, suggesting that this phenotype is common for capsid binders. In addition the VP1 region containing the G149C substitution has not been associated with antiviral resistance before. Our results demonstrate that the phenotype and genotype of clinically relevant vapendavir-resistant picornavirus species is more complex than generally believed.

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“…4c; Hadfield et al, 1995Hadfield et al, , 1999Smith et al, 1986;Filman et al, 1989;Plevka et al, 2013). The WIN compound vapendavir has been tested in Phase IIb clinical trials for antirhinovirus activity and indeed showed a reduction of viral load; development is ongoing (Lanko et al, 2021). Zika virus is a positive-strand RNA virus.…”

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“…Development of antivirals against RV infections has been the aim of numerous studies (summarized in multiple recent reviews [72][73][74][75][76][77]). Amongst early antiviral strategies, virustargeting capsid-binding drugs (Pleconaril, Pirodavir, Vapendavir) showed efficacy on preventing virus entry [78,79], but posed issues of rapidly emerging drug resistance [80][81][82]. Other viral targets include conserved regions in the viral RNA-dependent RNA polymerase and viral proteases (rupintrivir), but no drug has achieved approval for clinical use [83,84].…”

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“…Hence, it could slightly suppress EV-A71 RNA replication and protein synthesis, which insufficiently affects virion production. Pocapavir is an enterovirus-specific capsid inhibitor [ 33 ]. It has been used as an investigational drug for the treatment of severe neonatal enteroviral sepsis due to coxsackievirus B3 [ 42 ].…”

“…Moreover, Pocapavir has been reported for clearance of vaccine-derived type 3 poliovirus infection in an infant with underlying X-linked agammaglobulinemia [ 44 ]. The binding site of Pocapavir is within the pocket located in the structural protein VP1, namely canyon [ 33 ]. The Pocapavir binding results in an increase in the stability of the viral capsid, thus preventing conformational changes necessary for receptor interaction and uncoating.…”