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

Y Q Shirleen Soh,Jesse D Bloom,Rachel T Eguia,Keara D Malone

doi:10.3390/v13071196

Y Q Shirleen Soh, Jesse D Bloom + Show 2 more

Open Access

https://doi.org/10.3390/v13071196

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Journal: Viruses	Publication Date: Jun 22, 2021
Citations: 10	License type: CC BY 4.0

Affiliation: Howard Hughes Medical Institute, Fred Hutch Cancer Center

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.

Highlights

Viruses 2021, 13, 1196. https://Antivirals are an important prophylactic and treatment for influenza, for high-risk patients and those with severe infections [1]
The first influenza antivirals approved over two decades ago are the adamantanes, which target the matrix 2 (M2) ion channel of influenza A viruses, and neuraminidase inhibitors (NAIs), which inhibit the viral enzyme that facilitates the release of viral progeny from infected cells [3]
NAIs remain the standard of care, though resistance has been shown to emerge in some patients [5], and went to fixation in the extinct lineage of H1N1 influenza that circulated in humans prior to

Summary

Introduction

Viruses 2021, 13, 1196. https://Antivirals are an important prophylactic and treatment for influenza, for high-risk patients and those with severe infections [1]. The first influenza antivirals approved over two decades ago are the adamantanes, which target the matrix 2 (M2) ion channel of influenza A viruses, and neuraminidase inhibitors (NAIs), which inhibit the viral enzyme that facilitates the release of viral progeny from infected cells [3]. Their clinical use, has been impacted by the emergence of resistance mutations. NAIs remain the standard of care, though resistance has been shown to emerge in some patients [5], and went to fixation in the extinct lineage of H1N1 influenza that circulated in humans prior to

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