title: Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.
abstract: Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: María D
authors.initials: MD
authors.lastname: Duque
authors.forename: Chunlong
authors.initials: C
authors.lastname: Ma
authors.forename: Eva
authors.initials: E
authors.lastname: Torres
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Jordi
authors.initials: J
authors.lastname: Juárez-Jiménez
authors.forename: Pelayo
authors.initials: P
authors.lastname: Camps
authors.forename: F Javier
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 / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D009980:Influenza A virus / Q000187:drug effects / Q000254:growth & development; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010948:Viral Plaque Assay; D014981:Xenopus; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins