ArticleJournal of the American Chemical Society2011
Specific binding of adamantane drugs and direction of their polar amines in the pore of the influenza M2 transmembrane domain in lipid bilayers and dodecylphosphocholine micelles determined by NMR spectroscopy.
Article in Journal of the American Chemical Society, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers, 1 of them a synthesis that pooled it.
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Who cites it
70 citing papers in PubMed, 1 synthesis or guideline pooled it, 107 citations in OpenAlex.
- Amantadine and rimantadine for influenza A in children and the elderly.The Cochrane database of systematic reviews · 2014Pooled it
- Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches.RSC medicinal chemistry · 2026Review
- 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
- Distal protein-protein interactions contribute to nirmatrelvir resistance.Nature communications · 2025Article
- Oligomeric State and Drug Binding of the SARS-CoV-2 Envelope Protein Are Sensitive to the Ectodomain.Journal of the American Chemical Society · 2024Article
- Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors.Journal of medicinal chemistry · 2023Article
- Hexamethylene amiloride binds the SARS-CoV-2 envelope protein at the protein-lipid interface.Protein science : a publication of the Protein Society · 2023Article
- Antiviral Approaches against Influenza Virus.Clinical microbiology reviews · 2023Review
- Clustering of tetrameric influenza M2 peptides in lipid bilayers investigated byBiochimica et biophysica acta. Biomembranes · 2022Article
- Drug-Repurposing Screening Identified Tropifexor as a SARS-CoV-2 Papain-like Protease Inhibitor.ACS infectious diseases · 2022Article
- Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors.Journal of medicinal chemistry · 2022Article
- Influenza AM2 Channel Oligomerization Is Sensitive to Its Chemical Environment.Analytical chemistry · 2021Article
- Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay.ACS central science · 2021Article
- Adamantyl Isothiocyanates as Mutant p53 Rescuing Agents and Their Structure-Activity Relationships.Journal of medicinal chemistry · 2021Article
- Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and FlipGFP-based reporter assay.bioRxiv : the preprint server for biology · 2021Article
- From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus.Frontiers in molecular biosciences · 2021Review
- Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs.Molecules (Basel, Switzerland) · 2020Article
- Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against MScience advances · 2020Article
- Increased Dissociation of Adamantanamines in Influenza A M2 S31N with Partial Block by Rimantadine.Biophysical journal · 2020Article
- Chemical Probes for Blocking of Influenza A M2 Wild-type and S31N Channels.ACS chemical biology · 2020Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The transmembrane domain of the influenza M2 protein (M2TM) forms a tetrameric proton channel important for the virus lifecycle. The proton-channel activity is inhibited by amine-containing adamantyl drugs amantadine and rimantadine, which have been shown to bind specifically to the pore of M2TM near Ser31. However, whether the polar amine points to the N- or C-terminus of the channel has not yet been determined. Elucidating the polar group direction will shed light on the mechanism by which drug binding inhibits this proton channel and will facilitate rational design of new inhibitors. In this study, we determine the polar amine direction using M2TM reconstituted in lipid bilayers as well as dodecylphosphocholine (DPC) micelles. (13)C-(2)H rotational-echo double-resonance NMR experiments of (13)C-labeled M2TM and methyl-deuterated rimantadine in lipid bilayers showed that the polar amine pointed to the C-terminus of the channel, with the methyl group close to Gly34. Solution NMR experiments of M2TM in DPC micelles indicate that drug binding causes significant chemical shift perturbations of the protein that are very similar to those seen for M2TM and M2(18-60) bound to lipid bilayers. Specific (2)H-labeling of the drugs permitted the assignment of drug-protein cross peaks, which indicate that amantadine and rimantadine bind to the pore in the same fashion as for bilayer-bound M2TM. These results strongly suggest that adamantyl inhibition of M2TM is achieved not only by direct physical occlusion of the channel, but also by perturbing the equilibrium constant of the proton-sensing residue His37. The reproduction of the pharmacologically relevant specific pore-binding site in DPC micelles, which was not observed with a different detergent, DHPC, underscores the significant influence of the detergent environment on the functional structure of this membrane protein.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.