Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.
PMID: 25899336
2015
European journal of medicinal chemistry
Abstract: However, some of the 14-azaheptacyclo[8.6.1.0(2,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels.
Abstract: Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.
Adamantane-resistant influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene mutations.
Abstract: To investigate the frequency and distribution of M2 g
Table: V27A
Discussion: It was reported that mutated viruses may either lose the ability to bind M2 ion channel blockers, as with the S31N or A30T amino acid substitutions, or bind the blockers but retain M2 function, as with amino acid replacements L26F or V27A at residue 26 or 27.
Discussion: The known mutations that confer adamantane resistance are L26F, V27A, A30T (A30V), S31N, G34E, and L38F.
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.
PMID: 25470189
2014
Journal of the American Chemical Society
Introduction: Corroborating observations in cell cultures, large-scale sequencing of transmissible viruses from 1918 to 2008 have identified only three major amantadine-resistant M2 mutants, S31N, V27A, and L26F.
Introduction: However, mutations surrounding the drug binding site, such as S31N, V27A, A30T, and L26F, lead to escape of drug inhibition.
Introduction: Nevertheless, progress has been made in designing inhibitors targeting the drug-resistant mutants of M2 guided by MD simulations- and NMR structures M2.- The designed small molecule channel blockers inhibit V27A, L26F
Viral M2 ion channel protein: a promising target for anti-influenza drug discovery.
PMID: 25342196
2014
Mini reviews in medicinal chemistry
Abstract: The biologically important compounds discovered using the scaffolds such as bisnoradmantane, noradamantane, triazine, spiroadamantane, isoxazole, amino alcohol, azaspiro, spirene, pinanamine, etc are reported to exhibit anti-influenza activity against wild or mutant type (S31N and V27A) of M2 proton channel protein.
Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus.
PMID: 24941437
2014
Journal of medicinal chemistry
Conclusion: The present work shows the feasibility of designing easily accessible compounds able to successfully inhibit the wt and the V27A and L26F variants of the A/M2 channels of influenza A
Table: V27A
Figure: Representation of compound 18 bound to (left) the wild-type M2 channel and its V27A variant (down and up orientations shown in middle and right panels, respectively).
Figure: Structures of Amt, Rmt, and Recently Developed Compounds with Potent Activity against A/M2-V27A Mutant Channelsa.
Figure: The IC50 values denote the reported 50% inhibitory concentrations on A/M2 wt, S31N, and V27A proton channel function.
Isolation and characterization of H9N2 influenza virus isolates from poultry respiratory disease outbreak.
Discussion: The M2 gene has been extensively studied for drug resistance several mutations are known to confer drug resistance; L26F, V27A, A30T, S31N, G34E, L38F (Schnell and Chou).
Molecular and phylogenetic analysis of matrix gene of avian influenza viruses isolated from wild birds and live bird markets in the USA.
PMID: 22958470
2013
Influenza and other respiratory viruses
Abstract: Of these 17 isolates, 16 had S31N change and one isolate had V27A mutation.
Result: Of these 17 isolates, 16 had S31N change and one isolate had V27A mutation (Table 2).
Discussion: High prevalence of S31N substitution in this study is in line with those observed earlier, as this substitution is considered to be the most common mutation conferring resistance to adamentanes 20 , whereas V27A mutation is rare in frequency (1 6%).
Discussion: Substitution at position 31 (S31N) in M2 protein was the most commonly observed substitution with 16 of the 17 isolate having this mutation, whereas only one isolate had V27A change.
An assay suitable for high throughput screening of anti-influenza drugs.
Abstract: Two potential inhibitors for M2 (V27A) mutant were verified using this method, which inhibit both the mutant and wild-type M2 channels.
Result: Another two compounds 180 and 206, which are more potent than 34 and 35 in inhibiting V27A in electrophysiology assay, show higher viral inhibition activities at 10 microM.
Result: As summarized in tabe1, Compound 180 and 206 appear to be the best two inhibitors for M2 (V27A) mutant ion channel, which exhib
Table: V27 A
Table: V27A
Figure: (C) Expression of AcGFP-M2 (V27A) fusion protein in the presence of a group of compounds to be screened as described in (A).
Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay.
Result: Amantadine did not increase the growth of the S31N and V27A strains (Figs 1C, 1D), as expected since these mutated channels are amantadine-resistant.
Result: Compound 16 showed significant activity against the V27A mutant (EC50 = 7 microM) and was inactive against S31N while all other compounds were inactive against V27A or
Result: cerevisiae strains were generated containing a multicopy plasmid for expression of the wild-type, S31N-mutated, or V27A-mutated M2 gene from the Udorn strain of influenza A controlled by the inducible GAL1 promoter (designated WT, S31N and V27A respectively), or an empty plasmid.
Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus.
PMID: 23437766
2013
Journal of medicinal chemistry
Introduction: V27A, L26F, and S31N have consistently comprised more than 99% of transmissible M2 mutants, among which S31N is now predominant in 98-100% of the transmissible amantadine-resistant H1N1, H5N1, and H3N2 strains isolated from humans, birds, and swine in the past decade.
Introduction: These compounds showed excellent activity for WT, and some were highly active against V27A and L26F.
Introduction: While we succeeded in inhibiting V27A and L26F, none of these compounds inhibited S31N.
IV mutation literature information.
PMID: 
2015
European journal of medicinal chemistry
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