Rescue of Functional CFTR Channels in Cystic Fibrosis: A Dramatic Multivalent Effect Using Iminosugar Cluster-Based Correctors

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...

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Published in:Chembiochem : a European journal of chemical biology 2013-10, Vol.14 (15), p.2050-2058
Main 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
Format: Article
Language:English
Subjects:
Cell Membrane
Cell Membrane - drug effects
Cell Membrane - metabolism
CFTR correctors
Cystic Fibrosis
Cystic Fibrosis - drug therapy
Cystic Fibrosis - genetics
Cystic Fibrosis - metabolism
Cystic Fibrosis - pathology
Cystic Fibrosis Transmembrane Conductance Regulator
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Drug Design
HL-60 Cells
Humans
Imino Sugars
Imino Sugars - chemistry
Imino Sugars - pharmacology
Imino Sugars - therapeutic use
iminosugars
Life Sciences
multivalency
Mutation
Protein folding
protein folding diseases
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Summary: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. Three is better than one: Iminosugar clusters displaying three copies of the clinical candidate miglustat lead to CFTR correctors that are superior by as much as two orders of magnitude. Trivalent iminosugars are up to 1000 times more potent than the corresponding monovalent models. These results provide the first description of a multivalent effect for correcting protein‐folding defects in cells.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.201300312