title: Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus.
abstract: Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona , Av. Joan XXIII s/n, Barcelona E-08028, Spain.
authors.forename: Matias
authors.initials: M
authors.lastname: Rey-Carrizo
authors.forename: Marta
authors.initials: M
authors.lastname: Barniol-Xicota
authors.forename: Chunlong
authors.initials: C
authors.lastname: Ma
authors.forename: Marta
authors.initials: M
authors.lastname: Frigolé-Vivas
authors.forename: Eva
authors.initials: E
authors.lastname: Torres
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Salomé
authors.initials: S
authors.lastname: Llabrés
authors.forename: Jordi
authors.initials: J
authors.lastname: Juárez-Jiménez
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Luque
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lamb
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Pinto
authors.forename: Santiago
authors.initials: S
authors.lastname: Vázquez
mesh_terms: D000547:Amantadine / Q000031:analogs & derivatives*; D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D024882:Drug Resistance, Viral; D009980:Influenza A virus / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D009154:Mutation; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D018408:Patch-Clamp Techniques; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014981:Xenopus; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000588:Amines; D007473:Ion Channels; D011759:Pyrrolidines; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins