tetano
Editor, Senior Moderator
J Med Chem. 2017 Apr 18. doi: 10.1021/acs.jmedchem.6b01758. [Epub ahead of print]
[h=1]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.[/h] Barniol-Xicota M, Gazzarrini S, Torres E, Hu Y, Wang J, Naesens L, Moroni A, Vazquez S.
[h=3]Abstract[/h] New insights on the amantadine resistance mechanism of the V27A mutant were obtained through the study of novel, easily accessible 4-(1- and 2-adamantyl)piperidines, identified as dual binders of the wild-type and V27A mutant M2 channels of influenza A virus. Their antiviral activity and channel blocking ability were determined using cell-based assays and two-electrode voltage clamp (TEVC) technique on M2 channels, respectively. In addition, electrophysiology experiments revealed two interesting findings: i) these inhibitors display a different behaviour against the wild-type versus V27A mutant A/M2 channels and, ii) the compounds display antiviral activity when have kd equal or smaller than 10-6 while do not exhibit antiviral activity when kd is 10-5 or higher although may show blocking activity in the TEV assay. Thus caution must be taken when predicting antiviral activity based on percent channel blockage in electrophysiological assays. These findings provide experimental evidence of the resistance mechanism of the V27A mutation to wild-type inhibitors, previously predicted in silico, offer an explanation for the lack of antiviral activity of compounds active in the TEV assay, and may help design new and more effective drugs.
PMID: 28418242 DOI: 10.1021/acs.jmedchem.6b01758
[h=1]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.[/h] Barniol-Xicota M, Gazzarrini S, Torres E, Hu Y, Wang J, Naesens L, Moroni A, Vazquez S.
[h=3]Abstract[/h] New insights on the amantadine resistance mechanism of the V27A mutant were obtained through the study of novel, easily accessible 4-(1- and 2-adamantyl)piperidines, identified as dual binders of the wild-type and V27A mutant M2 channels of influenza A virus. Their antiviral activity and channel blocking ability were determined using cell-based assays and two-electrode voltage clamp (TEVC) technique on M2 channels, respectively. In addition, electrophysiology experiments revealed two interesting findings: i) these inhibitors display a different behaviour against the wild-type versus V27A mutant A/M2 channels and, ii) the compounds display antiviral activity when have kd equal or smaller than 10-6 while do not exhibit antiviral activity when kd is 10-5 or higher although may show blocking activity in the TEV assay. Thus caution must be taken when predicting antiviral activity based on percent channel blockage in electrophysiological assays. These findings provide experimental evidence of the resistance mechanism of the V27A mutation to wild-type inhibitors, previously predicted in silico, offer an explanation for the lack of antiviral activity of compounds active in the TEV assay, and may help design new and more effective drugs.
PMID: 28418242 DOI: 10.1021/acs.jmedchem.6b01758