Fluorinated chaperone-ß-cyclodextrin formulations for ß-glucocerebrosidase activity enhancement in neuronopathic Gaucher disease

Description

Amphiphilic glycomimetics encompassing a rigid, undistortable nor-tropane skeleton based on 1,6-anhydro-L-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β- glucocerebrosidase mutants associated to the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts. The body of work here presented includes the design criteria for the PC prototype, the synthesis of a series of candidates, the characterization of the PC:βCD complexes, the determination of the selectivity profiles towards a panel of commercial and human lysosomal glycosidases, the evaluation of the chaperoning activity in type 1 (non-neuronopathic), 2 (acute neuronopathic) and 3 (adult neuronopathic) GD fibroblasts, the confirmation of the rescuing mechanism by immunolabeling and the analysis of the PC:GCase binding mode by docking experiments.

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Ministerio de Economı́a y Competitividad SAF2016-76083-R, CTQ2015-64425-C2-1-R, BFU2015-71017-P, CTQ2013-43310

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Ministerio de Sanidad FIS PI13/00129

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Junta de Andalucı́a CTS-5725, FQM2012-1467, BIO-198

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Generalitat Valenciana PROMETEOII/2014/073)

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Ministry of Education, Culture, Science, Sports and Technology of Japan KAKENHI

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Ministry of Health, Labour and Welfare of Japan H17-Kokoro-019, H20-Kokoro-022

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European Union Seventh Framework Programme FP7-People-2012-CIG

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Marie Curie Reintegration 333594 E.M.S.-F

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European Regional Development Funds FEDER and FSE

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