ArticleJournal of the American Chemical Society2014
Flipping in the pore: discovery of dual inhibitors that bind in different orientations to the wild-type versus the amantadine-resistant S31N mutant of the influenza A virus M2 proton channel.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 103 citations in OpenAlex.
- Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches.RSC medicinal chemistry · 2026Review
- 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
- Mining Druggable Sites in Influenza A Hemagglutinin: Binding of the Pinanamine-Based Inhibitor M090.ACS medicinal chemistry letters · 2025Article
- Real-time tracking of drug binding to influenza A M2 reveals a high energy barrier.Journal of structural biology: X · 2023Article
- Emerging drug design strategies in anti-influenza drug discovery.Acta pharmaceutica Sinica. B · 2023Review
- Antiviral Approaches against Influenza Virus.Clinical microbiology reviews · 2023Review
- Synthesis and Crystal Structure of Adamantylated 4,5,6,7-Tetrahalogeno-1Molecules (Basel, Switzerland) · 2022Article
- MicroRNA-205-5p: A potential therapeutic target for influenza A.Journal of cellular and molecular medicine · 2022Article
- 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
- In Silico Evaluation of Hexamethylene Amiloride Derivatives as Potential Luminal Inhibitors of SARS-CoV-2 E Protein.International journal of molecular sciences · 2022Article
- Clustering of tetrameric influenza M2 peptides in lipid bilayers investigated byBiochimica et biophysica acta. Biomembranes · 2022Article
- Influenza AM2 Channel Oligomerization Is Sensitive to Its Chemical Environment.Analytical chemistry · 2021Article
- Rational design of a deuterium-containing M2-S31N channel blocker UAWJ280 withEmerging microbes & infections · 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
- Chemical Probes for Blocking of Influenza A M2 Wild-type and S31N Channels.ACS chemical biology · 2020Article
- Investigation of the Drug Resistance Mechanism of M2-S31N Channel Blockers through Biomolecular Simulations and Viral Passage Experiments.ACS pharmacology & translational science · 2020Article
- Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.PLoS pathogens · 2020Article
- Put a cork in it: Plugging the M2 viral ion channel to sink influenza.Antiviral research · 2020Review
- Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2020Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 1 country.
Funding
Abstract
Influenza virus infections lead to numerous deaths and millions of hospitalizations each year. One challenge facing anti-influenza drug development is the heterogeneity of the circulating influenza viruses, which comprise several strains with variable susceptibility to antiviral drugs. For example, the wild-type (WT) influenza A viruses, such as the seasonal H1N1, tend to be sensitive to antiviral drugs, amantadine and rimantadine, while the S31N mutant viruses, such as the pandemic 2009 H1N1 (H1N1pdm09) and seasonal H3N2, are resistant to this class of drugs. Thus, drugs targeting both WT and the S31N mutant are highly desired. We report our design of a novel class of dual inhibitors along with their ion channel blockage and antiviral activities. The potency of the most active compound 11 in inhibiting WT and the S31N mutant influenza viruses is comparable with that of amantadine in inhibiting WT influenza virus. Solution NMR studies and molecular dynamics (MD) simulations of drug-M2 interactions supported our design hypothesis: namely, the dual inhibitor binds in the WT M2 channel with an aromatic group facing down toward the C-terminus, while the same drug binds in the S31N M2 channel with its aromatic group facing up toward the N-terminus. The flip-flop mode of drug binding correlates with the structure-activity relationship (SAR) and has paved the way for the next round of rational design of broad-spectrum antiviral drugs.
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Registered trials
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