title: New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode.
abstract: Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.0(2,10).0(3,7).0(9,11)]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.0(2,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.
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.affiliation: Department of Biosciences and National Research Council (CNR) Biophysics Institute (IBF), University of Milan, Via Celoria 26, 20133 Milan, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Gazzarrini
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Prat de la Riba 171, Santa Coloma de Gramenet E-08921, Spain.
authors.forename: Salomé
authors.initials: S
authors.lastname: Llabrés
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: Marta
authors.initials: M
authors.lastname: Frigolé-Vivas
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Prat de la Riba 171, Santa Coloma de Gramenet E-08921, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Juárez-Jiménez
authors.affiliation: Unitat de Difracció de RX, Centres Científics i Tecnològics (CCiTUB), Universitat de Barcelona, Solé i Sabarís 1-3, Barcelona E-08028, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Font-Bardia
authors.affiliation: Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.affiliation: Department of Biosciences and National Research Council (CNR) Biophysics Institute (IBF), University of Milan, Via Celoria 26, 20133 Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Moroni
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Prat de la Riba 171, Santa Coloma de Gramenet E-08921, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
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. Electronic address: svazquez@ub.edu.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vázquez
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011083:Polycyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D000086082:Viroporin Proteins
chemical_list: D000998:Antiviral Agents; D011083:Polycyclic Compounds; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
keywords: Amantadine; Influenza A; M2 channel; Molecular dynamics; Polycyclic amines; V27A mutant