Scientific Results

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

Year: 2015

Authors: Parmeggiani C., Catarzi S., Matassini C., D’Adamio G., Morrone A., Goti A., Paoli P., Cardona F.

Autors Affiliation: Department of Chemistry “Ugo Schiff”, University of Florence;
CNR-INO, U.O.S. Sesto Fiorentino and LENS;
Paediatric Neurology Unit and Laboratories Neuroscience Department, Meyer Children’s Hospital and Department of Neurosciences, Pharmacology and Child Health University of Florence;
Department of Experimental and Clinical Biomedical Sciences University of Florence

Abstract: 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 beta-glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or a-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.

Journal/Review: CHEMBIOCHEM

Volume: 16 (14)      Pages from: 2054  to: 2064

More Information: This work was partially supported by grants from Italian Ministry of Health and Regione Toscana (Ricerca Finalizzata-2011-02347694), MIUR Italy (PRIN 2010-2011, 2010L9SH3K 006) and Ente Cassa di Risparmio di Firenze (project 2013/0366). We gratefully acknowledge the support of the Associazione Italiana Mucopolisaccaridosi e malattie affini (AIMPS) and the Associazione Malattie Metaboliche Congenite Ereditarie (AMMEC). The fibroblast cell line was obtained from the \”Cell Line and DNA Biobank from Patients Affected by Genetic Diseases\” (G. Gaslini Institute)-Telethon Network of Genetic Biobanks (Project No. GTB07001).
DOI: 10.1002/cbic.201500292

Citations: 23
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