Rescue of Functional CFTR Channels in Cystic Fibrosis: A Dramatic Multivalent Effect Using Iminosugar Cluster‐Based Correctors. Issue 15 (13th September 2013)

• Record Type: Journal Article
• Authors: Compain, Philippe; Decroocq, Camille; Joosten, Antoine; de Sousa, Julien; Rodríguez‐Lucena, David; Butters, Terry D.; Bertrand, Johanna; Clément, Romain; Boinot, Clément; Becq, Frédéric; Norez, Caroline
• Is Part Of: Chembiochem. Volume 14:Issue 15(2013)
• Page Start: 2050
• Page End: 2058
• Publication Date: 2013-09-13
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201300312
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Cystic fibrosis is caused by a mutation in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. <italic>N</italic>‐butyl 1‐deoxynojirimycin (<italic>N</italic>‐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 <italic>N</italic>‐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.</p> </abstract>