Fluorinated chaperone-ß-cyclodextrin formulations for ß-glucocerebrosidase activity enhancement in neuronopathic Gaucher disease
- García Moreno, M. Isabel
- Mata, Mario de la
- Sánchez Fernández, Elena Matilde
- Benito, Juan M.
- Díaz Quintana, Antonio Jesús
- Fustero, Santos
- Nanba, Eiji
- Higaki, Katsumi
- Sánchez-Alcazar, José Antonio
- García Fernández, José Manuel
- Ortiz Mellet, Carmen
DOIAbstract
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 p...