title: 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.
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.
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Chemistry, National Cheng-Kung University, 1, University Road, Tainan 701, Taiwan. Electronic address: wcheng@gate.sinica.edu.tw.
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Cheng
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Chemistry, National Cheng-Kung University, 1, University Road, Tainan 701, Taiwan.
authors.forename: Jen-Hon
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
authors.forename: Huang-Yi
authors.initials: HY
authors.lastname: Li
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
authors.forename: Sheng-Jhih
authors.initials: SJ
authors.lastname: Lu
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Hu
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Yun
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
authors.forename: Cheng-Hsin
authors.initials: CH
authors.lastname: Chiu
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Yang
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry; D056947:Enzyme Replacement Therapy / Q000379:methods*; D004795:Enzyme Stability / Q000187:drug effects; D000795:Fabry Disease / Q000188:drug therapy*; D006801:Humans; D050112:Imino Pyranoses / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D050111:Imino Sugars / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008353:Mannitol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D000519:alpha-Galactosidase / Q000187:drug effects*
chemical_list: C000614242:1-aminodeoxy-2,5-dideoxy-2,5-iminomannitol; D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; D050111:Imino Sugars; D011759:Pyrrolidines; D054852:Small Molecule Libraries; D008353:Mannitol; D000519:alpha-Galactosidase
keywords: Enzyme replacement therapy; Fabry disease; Lysosomal storage diseases; Lysosomal α-galactosidase A; Pharmacological chaperone; Pyrrolidine-based iminosugar