An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses.
Introduction: Genetic studies have shown that the predominant M2 mutants circulating among humans are S31N, V27A, and L26F.
Result: These results were expected since compounds 3, 7, and 16 were designed to target the M2-V27A mutant, not the M2-S31N mutant.
Result: When tested against the M2-
Discussion: Although the most frequent amantadine-resistant mutant M2-S31N remains partially sensitive to amantadine, the M2-V27A mutant was completely resistant to amantadine, which makes it a challenging drug target.
Drug-Resistant and Genetic Evolutionary Analysis of Influenza Virus from Patients During the 2013 and 2014 Influenza Season in Beijing.
PMID: 27203354
2017
Microbial drug resistance (Larchmont, N.Y.)
Abstract: All of the 23 samples with influenza A viruses harbored amantadine resistance mutation S31N in M2 matrix protein.
Biological fitness and natural selection of amantadine resistant variants of avian influenza H5N1 viruses.
Abstract: Here, using reverse genetics we investigated the biological impact of Ser31Asn in M2 commonly seen in viruses in clade 2.2.1.1 in farmed poultry in Egypt.
Abstract: The prevalence of the amantadine resistance marker at position 31 (Ser31Asn) of the M2 protein increased over time.
Antigenic and genetic characterization of influenza viruses circulating in Bulgaria during the 2015/2016 season.
PMID: 28132927
2017
Infection, genetics and evolution
Result: As with the vast majority of A(H1N1)pdm09 viruses, M2 proteins carried S31N substitution associated with resistance to M2-channel blockers (amantadine and rimantadine).
Expeditious Lead Optimization of Isoxazole-Containing Influenza A Virus M2-S31N Inhibitors Using the Suzuki-Miyaura Cross-Coupling Reaction.
PMID: 28182419
2017
Journal of medicinal chemistry
Result: All of these compounds (9a, 9d, 9f, 9h, 9q, 9r, 9s, 9t, 9u, and 9v) also had potent channel blockage against the AM2-S31N channel (> 70% at 100 muM), which is consistent with their potent antiviral activity.
Result: All synthesized compounds were tested for channel blockage against the AM2-S31N proton channel and antiviral activity against the A/California/07/2009 (H1N1) virus using the two-electrode voltage clamp (TEVC) assay and plaque assay, respectively.
Result: Briefly, the AM2-S31N channel was expressed in the oocyte cell membrane and was activated by acidic pH (pH = 5.5), compound was added at 100 muM concentration and the channel conductance current at the two-minute time point was recorded.
Result: CHANNEL INHIBITION, ANTIVIRAL ACTIVITY, AND CYTOTOXICITY OF ISOXAZOLE-CONTAINING AM2-S31N INHIBITORS.
Result: Compound
Stereoselective synthesis of novel adamantane derivatives with high potency against rimantadine-resistant influenza A virus strains.
Abstract: Biological assays of the prepared compounds were performed on the rimantadine-resistant S31N mutated strains of influenza A - A/California/7/2009(H1N1)pdm09 and modern pandemic strain A/IIV-Orenburg/29-L/2016(H1N1)pdm09.
Design and expeditious synthesis of organosilanes as potent antivirals targeting multidrug-resistant influenza A viruses.
PMID: 28433777
2017
European journal of medicinal chemistry
Result: Channel blockage, antiviral efficacy, and cytotoxicity of organosilane-based AM2-S31N inhibitors.
Result: Compounds 5d and 5e both had slightly reduced percentage channel blockage against the AM2-S31N channel when compared with compound 5b, and both were also less potent than 5b in terms of their antiviral activity.
Result: However, the difference between compounds 5b and 10 was more obvious, with the organosilane 5b being more potent than its carbon analogue 10 in blocking the AM2-S31N channel (86.7 +- 0.7% versus 75.4 +- 2.3%).
Result: Molecular docking of organosilane 5b in the AM2-S31N channel.
Result: None of the compounds showed significant inhibition (>35%) against the AM2-WT channel, which was expected since these compounds were designed to target the drug-resistant AM2-S31N channe
Slow but Steady Wins the Race: Dissimilarities among New Dual Inhibitors of the Wild-Type and the V27A Mutant M2 Channels of Influenza A Virus.
PMID: 28418242
2017
Journal of medicinal chemistry
Introduction: Although several mutations appear to be viable in vitro, a recent analysis of 31,251 M2 protein sequences revealed that the most frequent Amt-resistant mutations in the circulating strains occur at position 31 (S31N) (~ 95%), followed by position 27 (V27A), while other mutations (L26F, A30T, G34E and L38F) were rare.
Introduction: Several findings add functional relevance to the V27A mutation: (i) among the most prevalent mutations, V27A is the only one proven to originate from drug selection pressure; (ii) while the S31N and L26F mutants are sensitive, to some extent, to Amt, this drug is completely in
Anti-influenza activity of diazaadamantanes combined with monoterpene moieties.
Abstract: Modelling these compounds against an influenza virus M2 ion channel predicted plausible binding modes to both the wild-type and the mutant (S31N).
Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus.
PMID: 28477572
2017
European journal of medicinal chemistry
Abstract: Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine.
Result: At 100 muM, neither of the three compounds significantly inhibited the wild type or S31N mutant M2 channel, thus excluding M2 inhibition as the antiviral mechanism of action in virus-infected MDCK cells (data not shown).
Result: The A/Virginia/ATCC3/2009 strain, which has an S31N mutant M2 protein alike most currently circulating influenza A strains, had marginal to no sensitivity to the adamantane-based M2-blockers.
IV mutation literature information.
PMID: 
2017
Antiviral research
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