Open AccessComprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil
Author(s) -
Hashimoto Takashi,
Baba Keiko,
Inoue Kae,
Okane Miyako,
Hata Satoshi,
Shishido Takao,
Naito Akira,
Wildum Steffen,
Omoto Shinya
Publication year - 2021
Publication title -
influenza and other respiratory viruses
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.743
H-Index - 57
eISSN - 1750-2659
pISSN - 1750-2640
DOI - 10.1111/irv.12821
Subject(s) - polymerase , virus , amino acid , protein subunit , biology , virology , influenza a virus , amino acid substitution , rna polymerase , peptide sequence , gene , microbiology and biotechnology , genetics , mutation , rna
Abstract Background Baloxavir marboxil (BXM) is an approved drug that selectively targets cap‐dependent endonuclease on PA subunit in the RNA polymerase complex of influenza A and B viruses. Amino acid substitutions at position 38 in the PA subunit were identified as a major pathway for reduced susceptibility to baloxavir acid (BXA), the active form of BXM. Additionally, substitutions found at positions E23, A37, and E199 in the PA subunit impact BXA susceptibility by less than 10‐fold. Methods We comprehensively evaluated the impact of novel amino acid substitutions identified in PA, PB1, and PB2 subunits in BXM clinical trials and influenza sequence databases by means of drug susceptibility and replicative capacity. Results PA/I38N in A(H1N1)pdm09 and PA/I38R in A(H3N2) were newly identified as treatment‐emergent substitutions in the CAPSTONE‐2 study. The I38N substitution conferred reduced susceptibility by 24‐fold, whereas replicative capacity of the I38N‐substituted virus was impaired compared with the wild‐type. The I38R‐substituted virus was not viable in cell culture. All other mutations assessed in this extensive study did not significantly affect BXA susceptibility (< 2.4‐fold change). Conclusion These results provide additional information on the impact of amino acid substitutions in the trimeric viral polymerase complex to BXA susceptibility and will further support influenza surveillance.