ArticleProceedings of the National Academy of Sciences of the United States of America2016
Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 58 citations in OpenAlex.
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- Restriction endonuclease selective inhibition by β-cyclodextrin sulfate.Bioscience reports · 2025Article
- Genomic signatures and host adaptation of H5N1 clade 2.3.4.4b: A call for global surveillance and multi-target antiviral strategies.Current research in microbial sciences · 2025Article
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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.PLoS pathogens · 2022Article
- Structural and Biochemical Basis for Development of Diketo Acid Inhibitors Targeting the Cap-Snatching Endonuclease of the Ebinur Lake Virus (Order:Journal of virology · 2022Article
- Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins.Acta pharmaceutica Sinica. B · 2022Review
- Not making the cut: Techniques to prevent RNA cleavage in structural studies of RNase-RNA complexes.Journal of structural biology: X · 2022Review
- Identification of Influenza PAMolecules (Basel, Switzerland) · 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
- ImprovedFrontiers in microbiology · 2021Article
- Anti-Influenza Drug Discovery and Development: Targeting the Virus and Its Host by All Possible Means.Advances in experimental medicine and biology · 2021Article
- Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
The influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes host pre-mRNAs to serve as primers for viral mRNA and is an attractive target for antiinfluenza drug discovery. Compound L-742,001 is a prototypical endonuclease inhibitor, and we found that repeated passaging of influenza virus in the presence of this drug did not lead to the development of resistant mutant strains. Reduced sensitivity to L-742,001 could only be induced by creating point mutations via a random mutagenesis strategy. These mutations mapped to the endonuclease active site where they can directly impact inhibitor binding. Engineered viruses containing the mutations showed resistance to L-742,001 both in vitro and in vivo, with only a modest reduction in fitness. Introduction of the mutations into a second virus also increased its resistance to the inhibitor. Using the isolated wild-type and mutant endonuclease domains, we used kinetics, inhibitor binding and crystallography to characterize how the two most significant mutations elicit resistance to L-742,001. These studies lay the foundation for the development of a new class of influenza therapeutics with reduced potential for the development of clinical endonuclease inhibitor-resistant influenza strains.
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Registered trials
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