title: Discovery of Multitarget Agents Active as Broad-Spectrum Antivirals and Correctors of Cystic Fibrosis Transmembrane Conductance Regulator for Associated Pulmonary Diseases.
abstract: Enteroviruses (EVs) are among the most frequent infectious agents in humans worldwide and represent the leading cause of upper respiratory tract infections. No drugs for the treatment of EV infections are currently available. Recent studies have also linked EV infection with pulmonary exacerbations, especially in cystic fibrosis (CF) patients, and the importance of this link is probably underestimated. The aim of this work was to develop a new class of multitarget agents active both as broad-spectrum antivirals and as correctors of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding defect responsible for >90% of CF cases. We report herein the discovery of the first small molecules able to simultaneously act as correctors of the F508del-CFTR folding defect and as broad-spectrum antivirals against a panel of EVs representative of all major species.
authors.affiliation: P4T Group, Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma , Viale delle Scienze, 27/A, 43124 Parma, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Tassini
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000, Leuven, Belgium.
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000, Leuven, Belgium.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lanko
authors.affiliation: Istituto di Genetica Molecolare , IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London , Gower Street, WC1E 6BT London, U.K.
authors.forename: Emily
authors.initials: E
authors.lastname: Langron
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.|Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Falchi
authors.affiliation: Istituto di Genetica Molecolare , IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Kissova
authors.affiliation: Istituto di Genetica Molecolare , IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Armijos-Rivera
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000, Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Delang
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000, Leuven, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Mirabelli
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: P4T Group, Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma , Viale delle Scienze, 27/A, 43124 Parma, Italy.
authors.forename: Marco
authors.identifier: 0000-0001-9190-3712
authors.initials: M
authors.lastname: Pieroni
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.|Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: P4T Group, Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma , Viale delle Scienze, 27/A, 43124 Parma, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.affiliation: Istituto di Genetica Molecolare , IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London , Gower Street, WC1E 6BT London, U.K.
authors.forename: Paola
authors.initials: P
authors.lastname: Vergani
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: P4T Group, Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma , Viale delle Scienze, 27/A, 43124 Parma, Italy.
authors.forename: Marco
authors.identifier: 0000-0002-0874-6697
authors.initials: M
authors.lastname: Radi
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000821:virology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics*; D055808:Drug Discovery; D004770:Enterovirus / Q000187:drug effects*; D004769:Enterovirus Infections / Q000188:drug therapy / Q000235:genetics / Q000821:virology; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D017510:Protein Folding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D054852:Small Molecule Libraries; D019005:Cystic Fibrosis Transmembrane Conductance Regulator