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: Univ Florence, Dept Chem Ugo Schiff, I-50019 Sesto Fiorentino, Italy; CNR INO, UOS Sesto Fiorentino, I-50019 Sesto Fiorentino, Italy; CNR INO, LENS, I-50019 Sesto Fiorentino, Italy; Univ Florence, Meyer Childrens Hosp, Paediat Neurol Unit, I-50139 Florence, Italy; Univ Florence, Meyer Childrens Hosp, Labs Neurosci Dept, I-50139 Florence, Italy; Univ Florence, Dept Neurosci Pharmacol & Child Hlth, I-50139 Florence, Italy; Univ Florence, Dept Expt & Clin Biomed Sci, I-50134 Florence, Italy.
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).KeyWords: Gaucher disease; GCase inhibition; iminosugars; natural products; synthesisDOI: 10.1002/cbic.201500292ImpactFactor: 2.850Citations: 48data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2024-11-10References taken from IsiWeb of Knowledge: (subscribers only)Connecting to view paper tab on IsiWeb: Click hereConnecting to view citations from IsiWeb: Click here