Fluorinated Chaperone−β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease
| Autor: | Antonio Díaz-Quintana, Eiji Nanba, José M. García Fernández, Elena M. Sánchez-Fernández, José Antonio Sánchez-Alcázar, Carmen Ortiz Mellet, M. Isabel García-Moreno, Katsumi Higaki, Juan M. Benito, Mario de la Mata, Santos Fustero |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Generalitat Valenciana, Ministry of Education, Culture, Sports, Science and Technology (Japan), Ministry of Health, Labour and Welfare (Japan), European Commission |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Stereochemistry Mutant Neuronopathic Gaucher Disease 03 medical and health sciences Glucocerebrosidase activity Drug Discovery Amphiphile Humans In patient Nucleotide Cells Cultured chemistry.chemical_classification Gaucher Disease biology Cyclodextrin Chemistry beta-Cyclodextrins Fluorine 3. Good health Molecular Docking Simulation 030104 developmental biology Biochemistry Chaperone (protein) biology.protein Glucosylceramidase Molecular Medicine Molecular Chaperones |
| Zdroj: | idUS. Depósito de Investigación de la Universidad de Sevilla instname Digital.CSIC. Repositorio Institucional del CSIC |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01550 |
| Popis: | 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. The Spanish Ministerio de Economıa y Competitividad (MINECO; Contracts SAF2016-76083-R, CTQ2015-64425-C2-1-R, BFU2015-71017-P, and CTQ2013-43310), the Spanish Ministerio de Sanidad (Contract FIS PI13/00129), the Junta de Andalucıa (Contracts CTS-5725, FQM2012-1467, and BIO-198), the Generalitat Valenciana (PROMETEOII/2014/073), the Ministry of Education, Culture, Science, Sports and Technology of Japan (KAKENHI), the Ministry of Health, Labour and Welfare of Japan (Grants H17-Kokoro-019, H20-Kokoro-022), and the European Union Seventh Framework Programme (FP7-People-2012-CIG), Grant 333594 (to E.M.S.-F., Marie Curie Reintegration Grant) are acknowledged. Cofinancing from the European Regional Development Funds (FEDER and FSE) is also acknowledged. K.H. was supported by Takeda Science Foundation. |
| Databáze: | OpenAIRE |
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