ArticleProceedings of the National Academy of Sciences of the United States of America2013
Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers.
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Who cites it
114 citing papers in PubMed, 222 citations in OpenAlex.
- Roles of the M2 protein of influenza A virus.Virus genes · 2026Review
- Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches.RSC medicinal chemistry · 2026Review
- Anti-influenza drugs targeting trimeric RNA polymerase complex: From development to clinics.Acta pharmaceutica Sinica. B · 2026Review
- From neuraminidase inhibitors to novel mechanisms: expanding therapeutic strategies against influenza.Frontiers in cellular and infection microbiology · 2026Review
- Development of an ultrahigh affinity, trimeric ACE2 biologic as a universal SARS-CoV-2 antagonist.Communications biology · 2025Article
- Evaluation of pandemic potential of the genotype 4 (G4) swine influenza virus usingThe Journal of general virology · 2025Article
- Avian Influenza Virus: Comparative Evolution as the Key for Predicting Host Tropism Expansion.Pathogens (Basel, Switzerland) · 2025Article
- Bat Influenza M2 Shows Functions Similar to Those of Classical Influenza A Viruses.Pathogens (Basel, Switzerland) · 2025Article
- Molecular biophysics and inhibition mechanism of influenza virus A M2 viroporin by adamantane-based drugs - Challenges in designing antiviral agents.Journal of structural biology: X · 2025Article
- Drug resistance and possible therapeutic options against influenza A virus infection over past years.Archives of microbiology · 2024Review
- Incompatible packaging signals and impaired protein functions hinder reassortment of bat H17N10 or H18N11 segment 7 with human H1N1 influenza A viruses.Journal of virology · 2024Article
- Influenza A virus resistance to 4'-fluorouridine coincides with viral attenuation in vitro and in vivo.PLoS pathogens · 2024Article
- Geographical distribution and evolutionary dynamics of H4Nx avian influenza viruses.Frontiers in microbiology · 2024Article
- Genetic, biological and epidemiological study on a cluster of H9N2 avian influenza virus infections among chickens, a pet cat, and humans at a backyard farm in Guangxi, China.Emerging microbes & infections · 2023Article
- The M2 proteins of bat influenza A viruses reveal atypical features compared to conventional M2 proteins.Journal of virology · 2023Article
- Synthesis of an amantadine-based novel Schiff base and its transition metal complexes as potential ALP, α-amylase, and α-glucosidase inhibitors.RSC advances · 2023Article
- A Novel Triple Reassortment H3N8 Avian Influenza Virus: Characteristics, Pathogenicity, and Transmissibility.Transboundary and emerging diseases · 2023Article
- Synthesis and Crystal Structure of Adamantylated 4,5,6,7-Tetrahalogeno-1Molecules (Basel, Switzerland) · 2022Article
- Essential Oils and Their Compounds as Potential Anti-Influenza Agents.Molecules (Basel, Switzerland) · 2022Review
- Ultrasensitive chemiluminescent neuraminidase probe for rapid screening and identification of small-molecules with antiviral activity against influenza A virus in mammalian cells.Chemical science · 2022Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered small-molecule drugs that inhibit S31N with potencies greater than amantadine's potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel.
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