Fluorinated Chaperone-β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease.
Amphiphilic glycomimetics encompassing a rigid, undistortable nortropane 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 with 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 toward a panel of commercial and human lysosomal glycosidases, the evaluation of the chaperoning activity in type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 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.
Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla , c/Profesor García González 1, 41011 Sevilla, Spain.
M Isabel
MI
García-Moreno
Centro Andaluz de Biología del Desarrollo (CABD), CSIC, Universidad Pablo de Olavide, and Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Carretera de Utrera Km 1, 41013 Sevilla, Spain.
Mario
M
de la Mata
Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla , c/Profesor García González 1, 41011 Sevilla, Spain.
Elena M
EM
Sánchez-Fernández
Instituto de Investigaciones Químicas (IIQ), CSIC, and Universidad de Sevilla, Avda. Américo Vespucio 49, E-41092 Sevilla, Spain.
Juan M
JM
Benito
Instituto de Investigaciones Químicas (IIQ), CSIC, and Universidad de Sevilla, Avda. Américo Vespucio 49, E-41092 Sevilla, Spain.
Antonio
A
Díaz-Quintana
Departamento de Química Orgánica, Universidad de Valencia , 46100 Burjassot, Spain.|Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe , 46012 Valencia, Spain.
Santos
0000-0002-7575-9439
S
Fustero
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , 86 Nishi-cho, Yonago 683-8503, Japan.
Eiji
E
Nanba
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , 86 Nishi-cho, Yonago 683-8503, Japan.
Katsumi
K
Higaki
Centro Andaluz de Biología del Desarrollo (CABD), CSIC, Universidad Pablo de Olavide, and Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Carretera de Utrera Km 1, 41013 Sevilla, Spain.
José A
JA
Sánchez-Alcázar
Instituto de Investigaciones Químicas (IIQ), CSIC, and Universidad de Sevilla, Avda. Américo Vespucio 49, E-41092 Sevilla, Spain.
José M
0000-0002-6827-0387
JM
García Fernández
Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla , c/Profesor García González 1, 41011 Sevilla, Spain.
Carmen
C
Ortiz Mellet
D002478:Cells, Cultured; D005461:Fluorine / Q000737:chemistry*; D005776:Gaucher Disease / Q000201:enzymology*; D005962:Glucosylceramidase / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D062105:Molecular Docking Simulation; D047392:beta-Cyclodextrins / Q000737:chemistry*
D018832:Molecular Chaperones; D047392:beta-Cyclodextrins; D005461:Fluorine; D005962:Glucosylceramidase