2017年3月
Fluorinated Chaperone-beta-Cyclodextrin Formulations for beta-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease
JOURNAL OF MEDICINAL CHEMISTRY
- 巻
- 60
- 号
- 5
- 開始ページ
- 1829
- 終了ページ
- 1842
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1021/acs.jmedchem.6b01550
- 出版者・発行元
- AMER CHEMICAL SOC
Amphiphilic glycomimetics encompassing a rigid, undistortable nortropane skeleton based on 1,6anhydro-L-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with beta-cydodextrin (beta CD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal beta-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:beta CD complexes, the determination of the selectivity profiles toward a panel of commercial 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.
- リンク情報
- ID情報
-
- DOI : 10.1021/acs.jmedchem.6b01550
- ISSN : 0022-2623
- eISSN : 1520-4804
- Web of Science ID : WOS:000396296100015