ArticleJournal of virology2013
Mutational analysis of the binding pockets of the diketo acid inhibitor L-742,001 in the influenza virus PA endonuclease.
Article in Journal of virology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 76 citations in OpenAlex.
- Carryover effects of baloxavir acid in human nasopharyngeal/pharyngeal swabs on infectious titer testing of influenza virus.Influenza and other respiratory viruses · 2020Trial
- Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses from humans in the United States, October 2024 to February 2025.Emerging microbes & infections · 2026Article
- Detection and characterization of antiviral-resistant viruses during the influenza season of 2024-25.Microbiology spectrum · 2026Article
- New determinant of influenza hemagglutinin cleavability identified through random mutagenesis for acid-stabilizing mutations.Microbiology spectrum · 2026Article
- Antiviral susceptibility monitoring: testing algorithm, methods, and findings for influenza season, 2023-2024.Antiviral research · 2025Article
- Epidemiological, phylogenetic, and pathogenicity analysis of H4 subtype avian influenza viruses in China, 2011-2022.Virologica Sinica · 2025Article
- Pharmacokinetics, safety, and tolerability of onradivir in participants with severe renal impairment and matched healthy control participants.Antimicrobial agents and chemotherapy · 2025Article
- Antiviral Susceptibility of Swine-Origin Influenza A Viruses Isolated from Humans, United States.Emerging infectious diseases · 2024Article
- Two amino acid residues in the N-terminal region of the polymerase acidic protein determine the virulence of Eurasian avian-like H1N1 swine influenza viruses in mice.Journal of virology · 2024Article
- Recent Advances in the Phytochemistry of Bryophytes: Distribution, Structures and Biological Activity of Bibenzyl and Bisbibenzyl Compounds.Plants (Basel, Switzerland) · 2023Review
- Recent Advances of Pyridinone in Medicinal Chemistry.Frontiers in chemistry · 2022Review
- Exploration of the 2,3-dihydroisoindole pharmacophore for inhibition of the influenza virus PA endonuclease.Bioorganic chemistry · 2021Article
- Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance.Cold Spring Harbor perspectives in medicine · 2021Review
- Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil.Influenza and other respiratory viruses · 2021Article
- Multiple polymerase acidic (PA) I38X substitutions in influenza A(H1N1)pdm09 virus permit polymerase activity and cause reduced baloxavir inhibition.The Journal of antimicrobial chemotherapy · 2021Article
- Structural insights into the substrate specificity of the endonuclease activity of the influenza virus cap-snatching mechanism.Nucleic acids research · 2021Article
- Article
- Detection of baloxavir resistant influenza A viruses using next generation sequencing and pyrosequencing methods.Antiviral research · 2020Article
- Reprogramming of the Antibacterial Drug Vancomycin Results in Potent Antiviral Agents Devoid of Antibacterial Activity.Pharmaceuticals (Basel, Switzerland) · 2020Article
- Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The influenza virus PA endonuclease, which cleaves capped host pre-mRNAs to initiate synthesis of viral mRNA, is a prime target for antiviral therapy. The diketo acid compound L-742,001 was previously identified as a potent inhibitor of the influenza virus endonuclease reaction, but information on its precise binding mode to PA or potential resistance profile is limited. Computer-assisted docking of L-742,001 into the crystal structure of inhibitor-free N-terminal PA (PA-Nter) indicated a binding orientation distinct from that seen in a recent crystallographic study with L-742,001-bound PA-Nter (R. M. DuBois et al., PLoS Pathog. 8:e1002830, 2012). A comprehensive mutational analysis was performed to determine which amino acid changes within the catalytic center of PA or its surrounding hydrophobic pockets alter the antiviral sensitivity to L-742,001 in cell culture. Marked (up to 20-fold) resistance to L-742,001 was observed for the H41A, I120T, and G81F/V/T mutant forms of PA. Two- to 3-fold resistance was seen for the T20A, L42T, and V122T mutants, and the R124Q and Y130A mutants were 3-fold more sensitive to L-742,001. Several mutations situated at noncatalytic sites in PA had no or only marginal impact on the enzymatic functionality of viral ribonucleoprotein complexes reconstituted in cell culture, consistent with the less conserved nature of these PA residues. Our data provide relevant insights into the binding mode of L-742,001 in the PA endonuclease active site. In addition, we predict some potential resistance sites that should be taken into account during optimization of PA endonuclease inhibitors toward tight binding in any of the hydrophobic pockets surrounding the catalytic center of the enzyme.
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