title: Rapid modifications of N-substitution in iminosugars: development of new β-glucocerebrosidase inhibitors and pharmacological chaperones for Gaucher disease.
abstract: The rapid discovery of β-glucocerebrosidase (GCase) inhibitors and pharmacological chaperones for Gaucher disease is described. The N-aminobutyl DNJ-based iminosugar was synthesized and conjugating with a variety of carboxylic acids to generate a N-diversely substituted iminosugar-based library. Several members of this library were found to be nanomolar-range inhibitors of GCase; the inhibition constant Ki of the most potent was found to be 71nM. Although these new molecules showed reasonable chaperoning activity (1.5- to 1.9-fold) in the N370S fibroblast of Gaucher patient-derived cell line, this was accompanies by a concomitant decrease in the cellular α-glucosidase activity, which might limit their further therapeutic potential. Next, newly developed N-substituents were assembled with pyrrolidine-based scaffolds to generate new molecules for further evaluation. The new 2,5-dideoxy-2,5-imino-d-mannitol (DMDP)-based iminosugar 22 was found to exhibit a satisfactory chaperoning activity to enhance GCase activity by 2.2-fold in Gaucher N370S cell line, without impairment of cellular α-glucosidase activity.
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan. wcheng@gate.sinica.edu.tw
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Cheng
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Weng
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Yun
authors.forename: Shang-Yu
authors.initials: SY
authors.lastname: Chang
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Fu-Yung
authors.initials: FY
authors.lastname: Huang
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005776:Gaucher Disease / Q000201:enzymology* / Q000473:pathology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D050111:Imino Sugars; D005962:Glucosylceramidase
keywords: Chemical chaperone; GCase inhibitor; Gaucher disease; Glycosidases; Iminosugar