Cheng W.-C.Wang J.-H.Li H.-Y.Lu S.-J.Hu J.-M.Yun W.-Y.Chiu C.-H.Yang W.-B.YIN-HSIU CHIENWUH-LIANG HWU2020-12-162020-12-1620160223-5234https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979643798&doi=10.1016%2fj.ejmech.2016.07.025&partnerID=40&md5=52876c24f6ccad10c80a92e4f6a68cc8https://scholars.lib.ntu.edu.tw/handle/123456789/525850A 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]SDG3alpha 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; Stereoisomerismjournal article10.1016/j.ejmech.2016.07.025274749192-s2.0-84979643798