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
Amantadine resistance among highly pathogenic avian influenza viruses (H5N1) isolated from India.
Abstract: Results of the study revealed resistance to amantadine in antiviral assay among four H5N1 viruses out of which two viruses had Serine 31 Asparagine (AGT-AAT i.e., S31N) mutation and two had Valine 27 Alanine (GTT-GCT i.e., V27A) mutation.
Abstract: The four resistant viruses not only exhibited significant difference in effective concentration 50% (EC50) values of amantadine hydrochloride from that of susceptible viruses (P < 0.0001) but also showed significant difference between two different types (S31N and V27A) of mutant viruses (P < 0.05).
Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus.
PMID: 26722757
2016
European journal of medicinal chemistry
Abstract: We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak.
Mechanism and Kinetics of Copper Complexes Binding to the Influenza A M2 S31N and S31N/G34E Channels.
Abstract: Here we report the first crystal structure of the S31N mutant crystallized using lipidic cubic phase crystallization techniques and solved to 1.59 A resolution.
Abstract: In recent decades mutations have arisen in M2 that prevent the adamantanes from binding to the channel pore, with the most prevalent of these mutations being S31N.
Design of Broad-Spectrum Inhibitors of Influenza A Virus M2 Proton Channels: A Molecular Modeling Approach.
PMID: 27146707
2016
Current computer-aided drug design
Abstract: CONCLUSION: Using the molecular dynamics and molecular docking techniques, we have refined the dynamic dimer-ofdimers structures of the WT, S31N and V27A variants of the M2 proton channel of the influenza A virus, analyzed the inhibitor binding sites, identified a number of potential broad-spectrum inhibitor structures targeting them, and clarified the binding modes and probable mechanisms of action of one promising compound.
Abstract: METHOD: The dynamic dimer-of-dimers structures of the three primary M2 target variants, wild-type, S31N and V27A, were modeled by molecular dynamics and thoroughly analyzed in order to define the inhibitor binding sites.
[Genomic characteristics of 2 strains of influenza A(H9N2)virus isolated from human infection cases in Anhui province].
PMID: 27188368
2016
Zhonghua liu xing bing xue za zhi
Abstract: The amino acid sequence alignment results showed that several mutations for human infection tropism presented in the two virus strains, including Q226L, H183N and E190T in HA; S31N in M2; 63-65 deletion in NA.
Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride.
Abstract: In addition, tert-butyl 4'-(carbamimidoylcarbamoyl)-2',3-dinitro-[1,1'-biphenyl]-4-carboxylate ( 27: ) acts both on adamantane-sensitive and a resistant M2 variant encoding a serine to asparagine 31 mutation (S31N) with improved efficacy over amantadine and HMA (IC50 = 0.6 microM and 4.4 microM, respectively).
Abstract: Whereas 9: inhibited in vitro replication of influenza virus encoding wild-type M2 (EC50 = 2.3 microM), both 27: and tert-butyl 4'-(carbamimidoylcarbamoyl)-2',3-dinitro-[1,1'-biphenyl]-4-carboxylate ( 26: ) preferentially inhibited viruses encoding M2(S31N) (respective EC50 = 18.0 and 1.5 microM).
Sensitive Detection and Simultaneous Discrimination of Influenza A and B Viruses in Nasopharyngeal Swabs in a Single Assay Using Next-Generation Sequencing-Based Diagnostics.
Abstract: Of the influenza A viruses, 66.7% of A(H3N2) viruses tested had a E627K mutation in the PB2 protein, and 87.8% of the influenza A viruses contained the S31N mutation in the M2 protein.
Introduction: Current methods that evaluate antiviral resistance require two independent tests for the S31N substitutions conferring amantadine-resistance and the H274Y substitution conferring oseltamivir-resistance.
Discussion: Sequence analysis of 123 influenza A viruses revealed that 66.7%(82/123) of A(H3N2) viruses had a single signature mutation of E627K in the PB2 protein, and 88%(108/123) of influenza A(H3N2 and pdH1N1) viruses contained the S31N mutation in the
Mechanism and Kinetics of Copper Complexes Binding to the Influenza A M2 S31N and S31N/G34E Channels.
Conclusion: However, our recent studies demonstrated that unlike amantadine, M2-S31N channel blockers have a higher genetic barrier of drug resistance that is comparable to oseltamivir.
Conclusion: In addressing this unmet medical need, we revisited the M2 proton channel and aim to develop the next generation of antivirals by targeting the M2-S31N mutant.
Conclusion: In this study, we developed a late-stage diversification synthesis strategy that enabled us to expeditiously synthesize a focused library of M2-S31N inhibitors.
Conclusion: It was found that a hydrophobic substitution, preferentially piperidine and azepane, is required at the para-position of the aromatic head group for potent M2-
Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins.
IV mutation literature information.
PMID: 
2017
Journal of medicinal chemistry
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