Human Acid β-Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease

• Published in: Chembiochem : a European journal of chemical biology 2015-09, Vol.16 (14), p.2054-2064
• Main Authors: Parmeggiani, Camilla, Catarzi, Serena, Matassini, Camilla, D'Adamio, Giampiero, Morrone, Amelia, Goti, Andrea, Paoli, Paolo, Cardona, Francesca
• Format: Article
• Language: English
• Subjects: Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gaucher disease; Gaucher Disease - drug therapy; Gaucher Disease - enzymology; GCase inhibition; Glucosylceramidase - antagonists & inhibitors; Glucosylceramidase - metabolism; Humans; Imino Sugars - chemistry; Imino Sugars - pharmacology; iminosugars; natural products; synthesis
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201500292

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. Carbohydrate‐derived iminosugars (pyrrolidine, piperidine, and pyrrolizidine) were evaluated as inhibitors of human GCase, the deficient enzyme in Gaucher disease. Two newly synthesized compounds inhibited GCase at sub‐micromolar concentration, and one was able to rescue the residual activity of N370/RecNcil mutated GCase in human fibroblasts up to 1.5‐fold.