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Abstract
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 (IC50 = 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 (IC50 = 0.6 µM and 4.4 µM, respectively). Whereas 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 EC50 = 18.0 and 1.5 µM). This finding 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.
Footnotes
- Received December 7, 2015.
- Accepted May 12, 2016.
This work was funded by a Canadian Institutes of Health Research Industry-Partnered Collaborative Research Operating Grant [IPR-124291] which was cofunded by Cardiome Pharma Corp., Vancouver, Canada. We also wish to acknowledge the support from Grand Challenges Canada [0487-01-10]. Grand Challenges Canada is funded by the Government of Canada and is dedicated to supporting Bold Ideas with Big Impact in global health.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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