Fluorinated Chaperone-β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease.
M Isabel García-MorenoMario de la MataElena M Sánchez-FernándezJuan M BenitoAntonio Díaz-QuintanaSantos FusteroEiji NanbaKatsumi HigakiJosé A Sánchez-AlcázarJosé Manuel García FernándezCarmen Ortiz MelletPublished in: Journal of medicinal chemistry (2017)
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.
Keyphrases
- endothelial cells
- replacement therapy
- liver failure
- heat shock
- extracellular matrix
- molecular dynamics
- molecular dynamics simulations
- ionic liquid
- copy number
- dna methylation
- nk cells
- high resolution
- heat shock protein
- oxidative stress
- protein protein
- acute respiratory distress syndrome
- quantum dots
- mass spectrometry
- aortic dissection
- induced pluripotent stem cells
- hepatitis b virus
- tandem mass spectrometry
- extracorporeal membrane oxygenation