ArticleAntiviral research2018
Profiling the in vitro drug-resistance mechanism of influenza A viruses towards the AM2-S31N proton channel blockers.
Article in Antiviral research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches.RSC medicinal chemistry · 2026Review
- Rational design and in vivo validation of capsid inhibitors for enterovirus D68.Nature communications · 2026Article
- Mammalian adaptation and zoonotic risk of influenza A viruses in companion animals.Journal of veterinary science · 2025Review
- Novel influenza A(H1N2) seasonal reassortant virus identified in a patient, Sweden, April 2025.Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin · 2025Article
- High resistance barrier and prophylactic protection in preclinical models of SARS-CoV-2 with two siRNA combination.Nucleic acids research · 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
- Differences in Oligomerization of the SARS-CoV-2 Envelope Protein, Poliovirus VP4, and HIV Vpu.Biochemistry · 2024Article
- The V223I substitution in hemagglutinin reduces the binding affinity to human-type receptors while enhancing the thermal stability of the H3N2 canine influenza virus.Frontiers in microbiology · 2024Article
- Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors.Journal of medicinal chemistry · 2023Article
- Differences in Oligomerization of the SARS-CoV-2 Envelope Protein, Poliovirus VP4, and HIV Vpu.bioRxiv : the preprint server for biology · 2023Article
- Rational design of a deuterium-containing M2-S31N channel blocker UAWJ280 withEmerging microbes & infections · 2021Article
- Rimantadine Binds to and Inhibits the Influenza A M2 Proton Channel without Enantiomeric Specificity.Biochemistry · 2021Article
- Investigation of the Drug Resistance Mechanism of M2-S31N Channel Blockers through Biomolecular Simulations and Viral Passage Experiments.ACS pharmacology & translational science · 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
- A Novel Capsid Binding Inhibitor Displays Potent Antiviral Activity against Enterovirus D68.ACS infectious diseases · 2019Article
- The L46P mutant confers a novel allosteric mechanism of resistance toward the influenza A virus M2 S31N proton channel blockers.Molecular pharmacology · 2019Article
- Validating Enterovirus D68-2AJournal of virology · 2019Article
- Structure-Property Relationship Studies of Influenza A Virus AM2-S31N Proton Channel Blockers.ACS medicinal chemistry letters · 2018Article
- Article
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3 authors.
Funding
Abstract
The majority of human influenza A viruses currently in circulation carry the amantadine-resistant AM2-S31N channel mutation. We previously discovered a series of AM2-S31N inhibitors with potent antiviral activity against both oseltamivir-sensitive and -resistant influenza A viruses. To understand the drug-resistance mechanism of AM2-S31N inhibitors, we performed serial viral passage experiments using the influenza virus A/California/07/2009 (H1N1) to select drug-resistant AM2 mutations against two representative AM2-S31N channel blockers (1 and 2). Unlike amantadine, which gives rise to resistance after a single passage, compounds 1 and 2 selected for partially resistant viruses at passages 05 and 04 with a V27I and L26I mutation, respectively. This appears to suggest compounds 1 and 2 have a higher genetic barrier to resistance than amantadine at least in cell culture. Passage with a higher drug concentration of compound 2 selected higher level resistant viruses with a double mutant L26I + A30T. The mechanism of resistance and replication fitness for mutant viruses were evaluated by electrophysiology, reverse genetics, growth kinetics, and competition assays. AM2-S31N/V27I and AM2-S31N/L26I channels achieved similar specific proton conductance as AM2-S31N, but the AM2-S31N/L26I/A30T triple mutant had drastically reduced specific proton conductance. Viral replication fitness of AM2-S31N/V27I and AM2-S31N/L26I double mutant viruses were similar to AM2-S31N containing viruses in cell culture. However, AM2-S31N/L26I/A30T viruses displayed attenuated growth as well as inability to compete with AM2-S31N viruses. The results herein offer insight regarding the resistance mechanism of AM2-S31N inhibitors, and may help guide the design of the next-generation of AM2-S31N inhibitors with a higher genetic barrier to drug resistance.
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