RT Journal Article
SR Electronic
T1 Mechanisms of action of novel influenza A/M2 viroporin inhibitors derived from hexamethylene amiloride
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.102731
DO 10.1124/mol.115.102731
A1 Pouria Hasani Jalily
A1 Jodene Eldstrom
A1 Scott C Miller
A1 Daniel C Kwan
A1 Sheldon S -H Tai
A1 Doug Chou
A1 Masahiro Niikura
A1 Ian Tietjen
A1 David Fedida
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/05/18/mol.115.102731.abstract
AB 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 (IC50s = 0.2 vs. 0.6 and 1.3 µM, 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 (IC50s = 0.6 μM and 4.4 μM, respectively). While 9 inhibited in vitro replication of influenza virus encoding wild-type M2 (EC50 = 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 EC50s = 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.