title: Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease.
abstract: The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells.
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: 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: 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: Jia-Ming
authors.initials: JM
authors.lastname: Hu
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000795:Fabry Disease / Q000188:drug therapy*; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D009154:Mutation; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013237:Stereoisomerism; D013696:Temperature; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D054852:Small Molecule Libraries; D000519:alpha-Galactosidase
keywords: Azasugar; Combinatorial chemistry; Fabry disease; Lysosomal α-galactosidase; Pharmacological chaperone; Polyhydroxylated pyrrolidine