Bioevaluation of sixteen ADMDP stereoisomers toward alpha-galactosidase A: Development of a new pharmacological chaperone for the treatment of Fabry disease and potential enhancement of enzyme replacement therapy efficiency
Journal
European Journal of Medicinal Chemistry
Journal Volume
123
Pages
14-20
Date Issued
2016
Author(s)
Cheng W.-C.
Wang J.-H.
Li H.-Y.
Lu S.-J.
Hu J.-M.
Yun W.-Y.
Chiu C.-H.
Yang W.-B.
Abstract
A unique molecular library consisting of all sixteen synthetic ADMDP (1-aminodeoxy-DMDP) stereoisomers has been prepared and evaluated for inhibitory activity against α-Gal A, and ability to impart thermal stabilization of this enzyme. The results of this testing led us to develop a novel pharmacological chaperone for the treatment of Fabry disease. 3-Epimer ADMDP was found to be an effective pharmacological chaperone, able to rescue α-Gal A activity in the lymphoblast of the N215S Fabry patient-derived cell line, without impairment of cellular β-galactosidase activity. When 3-epimer ADMDP was administered with rh-α-Gal A (enzyme replacement therapy) for the treatment of Fabry patient-derived cell lines, improvements in the efficacy of rh-α-Gal A was observed, which suggests this small molecule can also provide clinical benefit of enzyme replacement therapy in Fabry disease. ? 2016
SDGs
Other Subjects
alpha galactosidase; beta galactosidase; glycosidase inhibitor; recombinant human alpha galactosidase; unclassified drug; 1-aminodeoxy-2,5-dideoxy-2,5-iminomannitol; alpha galactosidase; enzyme inhibitor; iminosugar; mannitol; molecular library; pyrrolidine derivative; Article; carbon nuclear magnetic resonance; dose response; drug potency; drug potentiation; drug screening; drug synthesis; enzyme activity; enzyme inhibition; enzyme replacement; epimer; Fabry disease; human; human cell; IC50; isomer; lymphoblast; lysosome; nucleophilicity; pH; proton nuclear magnetic resonance; stereoisomerism; analogs and derivatives; chemistry; drug effects; enzyme replacement; enzyme stability; Fabry disease; molecular library; pharmacology; procedures; stereoisomerism; synthesis; tumor cell line; alpha-Galactosidase; Cell Line, Tumor; Enzyme Inhibitors; Enzyme Replacement Therapy; Enzyme Stability; Fabry Disease; Humans; Imino Pyranoses; Imino Sugars; Mannitol; Pyrrolidines; Small Molecule Libraries; Stereoisomerism
Publisher
Elsevier Masson SAS
Type
journal article