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

Abstract

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.