title: Rescue of functional CFTR channels in cystic fibrosis: a dramatic multivalent effect using iminosugar cluster-based correctors.
abstract: Cystic fibrosis is caused by a mutation in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. N-butyl 1-deoxynojirimycin (N-Bu DNJ), a clinical candidate for the treatment of cystic fibrosis, is able to act as a CFTR corrector by overcoming the processing defect of the mutant protein. To explore the potential of multivalency on CFTR correction activity, a library of twelve DNJ click clusters with valencies ranging from 3 to 14 were synthesized. Significantly, the trivalent analogues were found to be up to 225-fold more potent than N-Bu DNJ and up to 1000-fold more potent than the corresponding monovalent models. These results provide the first description of a multivalent effect for correcting protein folding defects in cells and should have application for the treatment of a number of protein folding disorders. Preliminary mechanistic studies indicated that CFTR correction activity enhancement was not due to a multivalent effect in ER-glucosidase inhibition or to a different mode of action of the multivalent iminosugars.
authors.affiliation: Laboratoire de Synthèse Organique et Molécules Bioactives, Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087 Strasbourg (France); Institut Universitaire de France, 103 Bd Saint-Michel, 75005 Paris (France). philippe.compain@unistra.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Compain
authors.forename: Camille
authors.initials: C
authors.lastname: Decroocq
authors.forename: Antoine
authors.initials: A
authors.lastname: Joosten
authors.forename: Julien
authors.initials: J
authors.lastname: de Sousa
authors.forename: David
authors.initials: D
authors.lastname: Rodríguez-Lucena
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Johanna
authors.initials: J
authors.lastname: Bertrand
authors.forename: Romain
authors.initials: R
authors.lastname: Clément
authors.forename: Clément
authors.initials: C
authors.lastname: Boinot
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D050111:Imino Sugars / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation
chemical_list: D050111:Imino Sugars; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR correctors; cystic fibrosis; iminosugars; multivalency; protein folding diseases