N-Substituted 5-amino-1-hydroxymethyl-cyclopentanetriols: A new family of activity promotors for a G M1 -gangliosidosis related human lysosomal β-galactosidase mutant

• Published in: Carbohydrate research Vol. 443-444; pp. 15 - 22
• Main Authors: Schalli, Michael, Tysoe, Christina, Fischer, Roland, Pabst, Bettina M, Thonhofer, Martin, Paschke, Eduard, Rappitsch, Tanja, Stütz, Arnold E, Tschernutter, Marion, Windischhofer, Werner, Withers, Stephen G
• Format: Journal Article
• Language: English
• Published: Netherlands 18.04.2017
• Subjects: beta-Galactosidase - antagonists & inhibitors; beta-Galactosidase - genetics; Cyclopentanes - chemical synthesis; Cyclopentanes - chemistry; Cyclopentanes - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gangliosidosis, GM1 - enzymology; Gangliosidosis, GM1 - genetics; Humans; Models, Molecular; Molecular Conformation; Mutation; Galactosidase inhibitor; Aminocyclopentane; G(M1)-Gangliosidosis; Carbafuranose; Pharmacological chaperone
• ISSN: 0008-6215; 1873-426X
• DOI: 10.1016/j.carres.2017.03.009

From 1,2;3,4-di-O-isopropylidene-α-D-galactopyranose, a series of highly functionalized (hydroxymethyl)cyclopentanes was easily available. In line with reports by Reymond and Jäger on similar structures, these amine containing basic carbasugars are potent inhibitors of β-D-galactosidases and, for the first time, could be shown to act as pharmacological chaperones for G -gangliosidosis-associated lysosomal acid β-galactosidase mutant R201C, thus representing a new structural type of pharmacological chaperones for this lysosomal storage disease.