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Rescue of Functional CFTR Channels in Cystic Fibrosis: A Dramatic Multivalent Effect Using Iminosugar Cluster‐Based Correctors
Author(s) -
Compain Philippe,
Decroocq Camille,
Joosten Antoine,
de Sousa Julien,
RodríguezLucena David,
Butters Terry D.,
Bertrand Johanna,
Clément Romain,
Boinot Clément,
Becq Frédéric,
Norez Caroline
Publication year - 2013
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201300312
Subject(s) - cystic fibrosis transmembrane conductance regulator , cystic fibrosis , iminosugar , chemistry , potentiator , mutant , transmembrane protein , protein folding , folding (dsp implementation) , biophysics , microbiology and biotechnology , biochemistry , gene , biology , pharmacology , genetics , receptor , enzyme , electrical engineering , engineering
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.