Effect of E23G/K, F36V, N37T, E119D, and E199G polymerase acidic protein substitutions on the replication and baloxavir susceptibility of influenza B viruses.

Baloxavir marboxil (baloxavir) is a highly effective, single-dose influenza therapeutic. Identification of molecular markers in the target polymerase acidic (PA) protein that can diminish baloxavir efficacy is an ongoing goal of the scientific community. In this study, we generated recombinant Victoria-lineage and Yamagata-lineage influenza B viruses (IBVs) containing 6 substitutions (E23G/K, F36V, N37T, E119D, and E199G) spanning the endonuclease domain of the PA. Although 5 of these PA substitutions negatively impacted in vitro polymerase activity and replication kinetics, particularly in the Victoria-lineage IBV background, viruses with E119D exhibited activity levels comparable to those of wild-type viruses. Moreover, only E119D moderately decreased the susceptibility of IBVs to baloxavir (resulting in ∼2.0-fold to 2.6-fold elevated EC50s); viruses with the other substitutions exhibited normal drug inhibition. These results show that E119D may reduce the baloxavir susceptibility of IBVs without compromising their replicative fitness. Overall, this study expands the molecular landscape of PA substitutions potentially affecting baloxavir efficacy against IBV. Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Philippe Noriel Q Pascua, Jeremy C Jones, Richard J Webby, Elena A Govorkova. Effect of E23G/K, F36V, N37T, E119D, and E199G polymerase acidic protein substitutions on the replication and baloxavir susceptibility of influenza B viruses. Antiviral research. 2022 Dec;208:105455

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PMID: 36328072

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