tetano
Editor, Senior Moderator
Mol Pharmacol. 2016 May 18. pii: mol.115.102731. [Epub ahead of print]
[h=1]Mechanisms of action of novel influenza A/M2 viroporin inhibitors derived from hexamethylene amiloride.[/h] Jalily PH[SUP]1[/SUP], Eldstrom J[SUP]1[/SUP], Miller SC[SUP]1[/SUP], Kwan DC[SUP]1[/SUP], Tai SS[SUP]2[/SUP], Chou D[SUP]1[/SUP], Niikura M[SUP]2[/SUP], Tietjen I[SUP]1[/SUP], Fedida D[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The increasing prevalence of influenza viruses with resistance to approved antivirals highlights the need for new anti-influenza therapeutics. Here we describe the functional properties of hexamethylene amiloride (HMA)-derived compounds that inhibit the wild-type and adamantane-resistant forms of the influenza A M2 ion channel. For example, 6-(azepan-1-yl)-N-carbamimidoylnicotinamide ( 9: ) inhibits amantadine-sensitive M2 currents with 3 to 6-fold greater potency than amantadine or HMA (IC[SUB]50[/SUB]s = 0.2 vs. 0.6 and 1.3 ?M, respectively). Compound 9: competes with amantadine for M2 inhibition, and molecular docking simulations suggest that 9: binds at site(s) that overlap with amantadine binding. 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 (IC[SUB]50[/SUB]s = 0.6 μM and 4.4 μM, respectively). While 9: inhibited in vitro replication of influenza virus encoding wild-type M2 (EC[SUB]50[/SUB] = 2.3 μM), both 27: and tert-butyl 4'-(carbamimidoylcarbamoyl)-2',3-dinitro-[1,1'-biphenyl]-4-carboxylate ( 26: ) preferentially inhibited viruses encoding M2(S31N) (respective EC[SUB]50[/SUB]s = 18.0 and 1.5 μM). This indicates that HMA derivatives can be designed to inhibit viruses with resistance to amantadine. Our study highlights the potential of HMA derivatives as inhibitors of drug-resistant influenza M2 ion channels.
The American Society for Pharmacology and Experimental Therapeutics.
[h=4]KEYWORDS:[/h] Antiviral drugs; Func. analysis receptor/ion channel mutants; Mass Spectroscopy; NMR; Nuclear Magnetic Resonance; Structure/function/mechanism
PMID: 27193582 [PubMed - as supplied by publisher] Free full text
[h=1]Mechanisms of action of novel influenza A/M2 viroporin inhibitors derived from hexamethylene amiloride.[/h] Jalily PH[SUP]1[/SUP], Eldstrom J[SUP]1[/SUP], Miller SC[SUP]1[/SUP], Kwan DC[SUP]1[/SUP], Tai SS[SUP]2[/SUP], Chou D[SUP]1[/SUP], Niikura M[SUP]2[/SUP], Tietjen I[SUP]1[/SUP], Fedida D[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The increasing prevalence of influenza viruses with resistance to approved antivirals highlights the need for new anti-influenza therapeutics. Here we describe the functional properties of hexamethylene amiloride (HMA)-derived compounds that inhibit the wild-type and adamantane-resistant forms of the influenza A M2 ion channel. For example, 6-(azepan-1-yl)-N-carbamimidoylnicotinamide ( 9: ) inhibits amantadine-sensitive M2 currents with 3 to 6-fold greater potency than amantadine or HMA (IC[SUB]50[/SUB]s = 0.2 vs. 0.6 and 1.3 ?M, respectively). Compound 9: competes with amantadine for M2 inhibition, and molecular docking simulations suggest that 9: binds at site(s) that overlap with amantadine binding. 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 (IC[SUB]50[/SUB]s = 0.6 μM and 4.4 μM, respectively). While 9: inhibited in vitro replication of influenza virus encoding wild-type M2 (EC[SUB]50[/SUB] = 2.3 μM), both 27: and tert-butyl 4'-(carbamimidoylcarbamoyl)-2',3-dinitro-[1,1'-biphenyl]-4-carboxylate ( 26: ) preferentially inhibited viruses encoding M2(S31N) (respective EC[SUB]50[/SUB]s = 18.0 and 1.5 μM). This indicates that HMA derivatives can be designed to inhibit viruses with resistance to amantadine. Our study highlights the potential of HMA derivatives as inhibitors of drug-resistant influenza M2 ion channels.
The American Society for Pharmacology and Experimental Therapeutics.
[h=4]KEYWORDS:[/h] Antiviral drugs; Func. analysis receptor/ion channel mutants; Mass Spectroscopy; NMR; Nuclear Magnetic Resonance; Structure/function/mechanism
PMID: 27193582 [PubMed - as supplied by publisher] Free full text