Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, DRUG-RESISTANT MUTANTS, PROTON CHANNEL, S31N MUTANT, PROTEIN, ANTIINFLUENZA, HEMAGGLUTININ, DIMERIZATION, PH, Amantadine, Animals, Antiviral Agents, Aza Compounds, Bridged-Ring Compounds, Dogs, Drug Design, Drug Resistance, Viral, Guanidines, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H3N2 Subtype, Inhibitory Concentration 50, Madin Darby Canine Kidney Cells, Mutation, Pyrrolidines, Structure-Activity Relationship, Viral Matrix Proteins, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.