Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil

Abstract

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Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission

“…Further, such studies could also elucidate the structural impacts of E23G/K on other subtypes, helping to explain why E23G has not been observed to occur naturally in A(H3N2) viruses and why it failed to result in a >3-fold EC 50 increase, the suggested threshold for BXA resistance [ 2 , 12 , 14 ]. Other substitutions at Glu23 may also influence BXM resistance, similar to the observations with I38X [ 18 , 37 ], but it will also be important to explore synergy between other BXA-associated PA substitutions like E23G/K/R, I38F/M/N/S, E199D/G, etc. Finally, the evidence for the contribution of E23X to influenza B virus infectivity is conflicting: E23K caused no EC 50 increase in recombinant B/Maryland/1/1959 virus [ 6 ], but it imparted a modest 2.6-fold EC 50 change accompanied by reduced polymerase activity and cell replication fitness in recombinant B/Phuket/3073/2013 virus [ 25 ].…”

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020

“…These substitutions alone have little or no effect on in vitro baloxavir susceptibility when present in other subtypes (PA marker table), but their combined effect has not been determined. Thirteen viruses had PA-A37S; this substitution did not alter baloxavir susceptibility in a recombinant A(H1N1) virus ( Hashimoto et al, 2021 ). Of nine A(H1N2)v viruses collected in the United States during these two periods, three were tested for NAI susceptibility and six were tested for baloxavir susceptibility; all were susceptible to NAIs and baloxavir.…”

Influenza antivirals and animal models

“…In vitro studies showed impaired replication fitness of variants carrying either the PA I38T, I38F, or I38M in H1N1 and H3N2 viruses while only the PA I38F was impaired in IBV. Additional PA mutations (E23G/K, A37T, and E199G) have been identified in vitro to have a significant but lesser impact on BXM susceptibility [59,60]. Variants harboring the PA I38T, I38F, or I38M mutations were prevalent in 2.2-9.7% of BXM recipients during phase 2 and phase 3 trials resulting in the initial delay of influenza symptoms but accompanied by prolonged virus shedding and rise in viral titers [52,53].…”