Abstract: Deep sequencing analysis revealed that 67% (n = 4/6) of the population treated with BXM single therapy (1 or 5 mg/kg) possessed the treatment-emergent PA-I38X AAS variants (I38T, I38S, and I38V).
Bilobetin, a novel small molecule inhibitor targeting influenza virus polymerase acidic (PA) endonuclease was screened from plant extracts.
Abstract: Dose-dependent inhibition assay showed that Epimedii folium can effectivity inhibit the PAN and PAN-I38T with IC50 of 11.23 and 26.03 muM, respectively.
Abstract: In 45 kinds of plant extracts, eight can effectively inhibit the PAN and PAN-I38T mutant in the primary screening.
Abstract: folium were virtually screened using the in silico method, and the compounds ginkgetin and bilobetin bind to the active pocket of PAN and PAN-I38T with a strong interaction force.
Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil.
PMID: 33099886
2021
Influenza and other respiratory viruses
Introduction: A(H1N1)pdm09 and A(H3N2) viruses harboring PA/I38T substitution were detected in some few subjects without prior BXM treatment, suggesting the possibility of human-to-human transmission of the variant viruses.
Introduction: Influenza surveillance studies conducted in Japan during the 2018-19 influenza season confirmed treatment-emergence of PA/I38T and PA/I38M variants in A(H3N2)-infected subjects.
Discussion: However, these substitutions were unable to restore the growth impairment of the I38T-substituted viruses.
Discussion: In addition, the replicative capacity of I38N viruses was reduced to a comparable level to I38T viruses.
Discussion: In this study, we characterized PA/I38 substitutions detected in clinical
Multiple polymerase acidic (PA) I38X substitutions in influenza A(H1N1)pdm09 virus permit polymerase activity and cause reduced baloxavir inhibition.
PMID: 33351916
2021
The Journal of antimicrobial chemotherapy
Abstract: PA I38T/M/F substitutions reduce its antiviral efficacy.
Synthesis, inhibitory activity and oral dosing formulation of AV5124, the structural analogue of influenza virus endonuclease inhibitor baloxavir.
PMID: 33367751
2021
The Journal of antimicrobial chemotherapy
Abstract: Notably, AV5116 was equipotent or more potent than baloxavir acid (BXA) against WT (I38-WT) viruses and viruses with reduced BXA susceptibility carrying an I38T polymerase acidic (PA) substitution.
The active form of the influenza cap-snatching endonuclease inhibitor baloxavir marboxil is a tight binding inhibitor.
PMID: 33647314
2021
The Journal of biological chemistry
Abstract: Here we studied the mechanisms underlying the high potency of BXA and how the I38T mutation confers resistance to the drug.
Abstract: The apparent inhibitor constant (Kiapp) is 12 nM, while the I38T mutation increased Kiapp by ~18-fold.
Abstract: The collective data support the conclusion that BXA is a tight binding inhibitor and the I38T mutation diminishes these properties.
Introduction: In a recent trial, I38T/M/F substitutions appeared in 9.7% of patients receiving BXM.
Introduction: Mutant viruses are associated with up to 50-fold increases in EC50 values with I38T showing the most significant effect.
Introduction: The biochemical data demonstrate that BXA can be classified as a tight binding inhibitor and that the I38T mutation
Favipiravir-resistant influenza A virus shows potential for transmission.
Discussion: Here a single mutation PA I38T gave resistance to baloxavir.
Discussion: The authors found that there was a fitness cost to the PA I38T mutation which reduced transmission in competition with WT in H1N1 and H3N2 viruses although in ferrets infected with 100% resistant virus, the PA I38T mutation could still transmit.
Development of cycling probe based real-time PCR methodology for influenza A viruses possessing the PA/I38T amino acid substitution associated with reduced baloxavir susceptibility.
Abstract: After baloxavir treatment, the most frequently detected substitution is Ile38Thr in polymerase acidic protein (PA/I38T), and this substitution reduces baloxavir susceptibility in influenza A viruses.
Abstract: Although human-to-human transmission of PA/I38T variant may have occurred in a closed environment, the prevalence of this variant in influenza A viruses was still limited.
Abstract: In addition, we found PA/I38T variant in siblings who did not received baloxavir treatment during an infection caused by A (H3N2) that afflicted the entire family.
Abstract: Our cycling probe-PCR system is thus useful for antiviral surveillance of influenza A viruses possessing PMID: 33679636
2021
Frontiers in microbiology
Figure: MDCK cells were infected (MOI = 0.001) with either wild type or PA-I38T mutant influenza virus (A) rgA/Giessen/6/2009 (H1N1) or (B) rgA/Victoria/3/75 (H3N2).
Discussion: Here we demonstrate that, despite the potent effect of BXA against both WT strains, its antiviral effect was significantly reduced by ~40% against the mutant strains, while ATR-002 still impaired the PA-I38T mutants to a similar extent as the respective wild type strains (Figure 3).
Discussion: In regard to comparability and to exclude unwanted additional mutations/differences, we generated these viruses as recombinant wild type and mutant variants (rgH1N1-WT/- PA-I38T, rgH3N2-WT/- PA-I38T) allowing us to perform unbiased comparison
Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial.
PMID: 32526195
2020
The Lancet. Infectious diseases
Abstract: Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.
IV mutation literature information.
PMID: 
2021
Antiviral research
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