Comprehensive Profiling of Mutations to Influenza Virus PB2 That Confer Resistance to the Cap-Binding Inhibitor Pimodivir

Abstract

Antivirals are used not only in the current treatment of influenza but are also stockpiled as a first line of defense against novel influenza strains for which vaccines have yet to be developed. Identifying drug resistance mutations can guide the clinical deployment of the antiviral and can additionally define the mechanisms of drug action and drug resistance. Pimodivir is a first-in-class inhibitor of the polymerase basic protein 2 (PB2) subunit of the influenza A virus polymerase complex. A number of resistance mutations have previously been identified in treated patients or cell culture. Here, we generate a complete map of the effect of all single-amino-acid mutations to an avian PB2 on resistance to pimodivir. We identified both known and novel resistance mutations not only in the previously implicated cap-binding and mid-link domains, but also in the N-terminal domain. Our complete map of pimodivir resistance thus enables the evaluation of whether new viral strains contain mutations that will confer pimodivir resistance.

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“…The compound pimodivir, which is a PB2 cap inhibitor, has entered the third phase of clinical trials. However, with the mutation of viral proteins, pimodivir has shown some resistance [ 122 , 123 ]. In addition to blocking the interaction between PB1 and PA, PA protein also represents an attractive target for new antiviral drugs because it is highly conserved.…”

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“…However, several major drug-mutations in the PB2 subunit has already been observed (such as F404Y and M431I and H357N, [42]) to show resistance. Thus, the mapping of PB2 single-amino-mutations could prepare against Pimodivir resistance [127]. For it is through predicting and understanding mutations that future inhibitors (or improvement on existing inhibitors such as Pimodivir) which could possibly withstand drug-resistance mutations [127] be better designed.…”

“…Thus, the mapping of PB2 single-amino-mutations could prepare against Pimodivir resistance [127]. For it is through predicting and understanding mutations that future inhibitors (or improvement on existing inhibitors such as Pimodivir) which could possibly withstand drug-resistance mutations [127] be better designed. This combinatorial approach of computational and experimental research has been previously applied in the COVID-19 pandemic, for both drug repurposing [128] and synergistic drug combinations [129].…”