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

AuthorsGarcía Moreno, María Isabel; Mata, Mario de la ; Sánchez-Fernández, Elena M. ; Benito, Juan M. ; Díaz-Quintana, Antonio; Fustero, Santos; Nanba, Eiji; Higaki, Katsumi; Sánchez-Alcázar, José Antonio ; García-Fernández, José Manuel; Ortiz-Mellet, Carmen
Issue Date2017
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 60(5): 1829-1842 (2017)
AbstractAmphiphilic 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.
Publisher version (URL)https://doi.org/10.1021/acs.jmedchem.6b01550
Identifiersdoi: 10.1021/acs.jmedchem.6b01550
issn: 0022-2623
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