Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.
PMID: 28418242
2017
Journal of medicinal chemistry
Result: As reference, Amt inhibited the wt A/M2 channel with an IC50 of 16.0 muM, while displaying much lower activity against the S31N mutant channel (IC50 of 200 muM), and being totally inactive against the V27A mutant.
Result: Compound 8, that did not inhibit the V27A channel (Table 1 and Figure 2H) but showed antiviral activity against the A/HK/7/87, was also assayed.
Result: Hence, although compounds 2 and 7 can bind the V27A channel (Table 1), i.
Result: In contrast, the inhibition of the V27A M2 mutant channel with 8 was already at steady-state after just 1 min (Figure 2H).
Result: In the case of the V27A mutant channel (right panels in Figure 2), compounds 2 and 7 had higher affi
Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.
Abstract: Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target.
Abstract: Compound 3 not only had single to sub-micromolar EC50 values against M2-WT- and M2-V27A-containing influenza A viruses in antiviral assays, but also rescued mice from lethal viral infection by either M2-WT- or M2-V27A-containing influenza A viruses.
Abstract: Guided by molecular dynamics simulations, we previously designed first-in-class M2-V27A inhibitors.
Mechanism of the Pseudoirreversible Binding of Amantadine to the M2 Proton Channel.
PMID: 27933932
2016
Journal of the American Chemical Society
Abstract: Finally, the results reveal that the thermodynamics and kinetics of Amt (un)binding is very sensitive to the V27A mutation, providing a quantitative rationale to the drastic decrease in inhibitory potency against the V27A variant.
Abstract: To this end, we have investigated the binding of amantadine (Amt) to the wild type (wt) M2 channel and its V27A variant using multiple independent molecular dynamics simulations, exploratory conventional metadynamics, and multiple-walkers well-tempered metadynamics calculations.
Discovery of Potent Antivirals against Amantadine-Resistant Influenza A Viruses by Targeting the M2-S31N Proton Channel.
Introduction: It is important to stress that although a large number of M2 mutants were selected from cell culture, animals, and human patients upon drug treatment, only a limited number of M2 mutants evolved the fitness of transmission among humans, namely V27A, S31N, and L26F.
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.
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).
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.
Influenza A viruses of swine circulating in the United States during 2009-2014 are susceptible to neuraminidase inhibitors but show lineage-dependent resistance to adamantanes.
Result: The S31N-M2 accounted for 78% (585/747) of resistant sequences alone and 22% (162/747) in combination with the V27A-M2 in the Eurasian avian lineage.
Result: The V27A-M2 occurred independently at least twice in 2009 [2009.9 (BCI 2010.20-2009.9) lineage D and 2009.50 (BCI 2010.0-2009.1) lineage E].
Result: This finding and the observation that V27A-M2 is present only in combination with S31N-M2 suggests that the emergence of the amantadine-resistant double mutant (S31N-M2 + V27A-M2) in the Eu
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.
Steered molecular dynamics approach for promising drugs for influenza A virus targeting M2 channel proteins.
Abstract: We have used steered molecular dynamics simulation to investigate the molecular interactions between four M2 inhibitors (amantadine, rimantadine, and two other amantadine derivatives) and the M2 protein channels of influenza A virus H5N1, including the wild type (WT) and three previously identified drug-resistant variants (G34A, S31N, and V27A).
IV mutation literature information.
PMID: 
2017
Journal of medicinal chemistry
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