Premium
A Systematic Investigation of Iminosugar Click Clusters as Pharmacological Chaperones for the Treatment of Gaucher Disease
Author(s) -
Joosten Antoine,
Decroocq Camille,
de Sousa Julien,
Schneider Jérémy P.,
Etamé Emile,
Bodlenner Anne,
Butters Terry D.,
Compain Philippe
Publication year - 2014
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.201300442
Subject(s) - iminosugar , glucocerebrosidase , chemical chaperone , chemistry , prodrug , acetylation , enzyme , chaperone (clinical) , biochemistry , combinatorial chemistry , stereochemistry , medicine , unfolded protein response , endoplasmic reticulum , pathology , gene
A series of 18 mono‐ to 14‐valent iminosugars with different ligands, scaffolds, and alkyl spacer lengths have been synthesized and evaluated as inhibitors and pharmacological chaperones of β‐glucocerebrosidase (GCase). Small but significant multivalent effects in GCase inhibition have been observed for two iminosugar clusters. Our study provides strong confirmation that compounds that display the best affinity for GCase are not necessarily the best chaperones. The best chaperoning effect observed for a deprotected iminosugar cluster has been obtained with a tetravalent 1‐deoxynojirimycin (DNJ) analogue (3.3‐fold increase at 10 μ M ). In addition, our study provides the first evidence of the high potential of prodrugs for the development of potent pharmacological chaperones. Acetylation of a trivalent DNJ derivative, to give the corresponding acetate prodrug, leads to a pharmacological chaperone that produces higher enzyme activity increases (3.0‐fold instead of 2.4‐fold) at a cellular concentration (1 μ M ) reduced by one order of magnitude.