ArticleThe Journal of antimicrobial chemotherapy2021
Multiple polymerase acidic (PA) I38X substitutions in influenza A(H1N1)pdm09 virus permit polymerase activity and cause reduced baloxavir inhibition.
Article in The Journal of antimicrobial chemotherapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- A Sequence-Based Update on Amino Acid Substitutions in Influenza Polymerase Acidic Protein in Europe That Alter Baloxavir Susceptibility From 2009 to 2025.Influenza and other respiratory viruses · 2026Article
- Article
- Pharmacophores of Influenza Virus PA Endonuclease Inhibitors.Advances in experimental medicine and biology · 2026Review
- A scoping review of influenza RdRp-targeting inhibitors: mechanisms, clinical translation, and emerging challenges.Frontiers in microbiology · 2026Review
- Bisbenzylisoquinoline alkaloids inhibit influenza virus replication by disrupting endosomal acidification.Virology journal · 2025Article
- Genotypic and phenotypic susceptibility of emerging avian influenza A viruses to neuraminidase and cap-dependent endonuclease inhibitors.Antiviral research · 2024Article
- Emergence of Eurasian Avian-Like Swine Influenza A (H1N1) virus in a child in Shandong Province, China.BMC infectious diseases · 2024Article
- Influenza A virus resistance to 4'-fluorouridine coincides with viral attenuation in vitro and in vivo.PLoS pathogens · 2024Article
- Impact of Baloxavir Resistance-Associated Substitutions on Influenza Virus Growth and Drug Susceptibility.Journal of virology · 2023Article
- Evolution of Influenza Viruses-Drug Resistance, Treatment Options, and Prospects.International journal of molecular sciences · 2022Review
- Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission.PLoS pathogens · 2022Article
- Pleiotropic Effects of Influenza H1, H3, and B Baloxavir-Resistant Substitutions on Replication, Sensitivity to Baloxavir, and Interferon Expression.Antimicrobial agents and chemotherapy · 2022Article
- Influenza polymerase inhibitor resistance: Assessment of the current state of the art - A report of the isirv Antiviral group.Antiviral research · 2021Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
backgroundBaloxavir marboxil is an antiviral drug that targets the endonuclease activity of the influenza virus polymerase acidic (PA) protein. PA I38T/M/F substitutions reduce its antiviral efficacy.
objectivesTo understand the effects of the 19 possible amino acid (AA) substitutions at PA 38 on influenza A(H1N1)pdm09 polymerase activity and inhibition by baloxavir acid, the active metabolite of baloxavir marboxil.
methodsInfluenza A(H1N1)pdm09 viral polymerase complexes containing all 19 I38X AA substitutions were reconstituted in HEK293T cells in a mini-replicon assay. Polymerase complex activity and baloxavir inhibitory activity were measured in the presence or absence of 50 nM baloxavir acid.
resultsOnly three substitutions (R, K, P) reduced polymerase activity to <79% of I38-WT. When compared with the prototypical baloxavir marboxil resistance marker T38, 5 substitutions conferred 10%-35% reductions in baloxavir acid inhibitory activity (M, L, F, Y, C) and 11 substitutions conferred >50% reductions (R, K, S, N, G, W, A, Q, E, D, H), while two substitutions (V, P) maintained baloxavir acid inhibitory activity.
conclusionsMost PA 38 substitutions permit a functional replication complex retaining some drug resistance in the mini-replicon assay. This study provides a targeted approach for virus rescue and analysis of novel baloxavir marboxil reduced-susceptibility markers, supports the consideration of a broader range of these markers during antiviral surveillance and adds to the growing knowledge of baloxavir marboxil resistance profiles.
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