Premium
Human Acid β‐Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease
Author(s) -
Parmeggiani Camilla,
Catarzi Serena,
Matassini Camilla,
D'Adamio Giampiero,
Morrone Amelia,
Goti Andrea,
Paoli Paolo,
Cardona Francesca
Publication year - 2015
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.201500292
Subject(s) - iminosugar , glucocerebrosidase , chemistry , pyrrolidine , enzyme , alkylation , biochemistry , piperidine , stereochemistry , catalysis
A collection of carbohydrate‐derived iminosugars belonging to three structurally diversified sub‐classes (polyhydroxylated pyrrolidines, piperidines, and pyrrolizidines) was evaluated for inhibition of human acid β‐glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or α‐carbon atom with alkyl chains of different lengths suggested an interpretation of the inhibition data and led to the discovery of two new GCase inhibitors at sub‐micromolar concentration. In the piperidine iminosugar series, two N‐alkylated derivatives were found to rescue the residual GCase activity in N370S/RecNcil mutated human fibroblasts (among which one up to 1.5‐fold). This study provides the starting point for the identification of new compounds in the treatment of Gaucher disease.