title: pH-Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases.
abstract: A general approach is reported for the design of small-molecule competitive inhibitors of lysosomal glycosidases programmed to 1) promote correct folding of mutant enzymes at the endoplasmic reticulum, 2) facilitate trafficking, and 3) undergo dissociation and self-inactivation at the lysosome. The strategy is based on the incorporation of an orthoester segment into iminosugar conjugates to switch the nature of the aglycone moiety from hydrophobic to hydrophilic in the pH 7 to pH 5 window, which has a dramatic effect on the enzyme binding affinity. As a proof of concept, new highly pH-responsive glycomimetics targeting human glucocerebrosidase or α-galactosidase with strong potential as pharmacological chaperones for Gaucher or Fabry disease, respectively, were developed.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla c/Profesor García González 1, 41011 Sevilla (Spain).
authors.forename: Teresa
authors.initials: T
authors.lastname: Mena-Barragán
authors.affiliation: Division of Child Neurology, Tottori University Faculty of Medicine, Yonago 683-8504 (Japan).
authors.forename: Aya
authors.initials: A
authors.lastname: Narita
authors.affiliation: Center for Biomedical Research, Depertamento de Ciencias, Biomedicas y Medicina/Programa de Medicina Regenerativa, Universidad do Algarve (Portugal).
authors.forename: Dino
authors.initials: D
authors.lastname: Matias
authors.affiliation: Center for Biomedical Research, Depertamento de Ciencias, Biomedicas y Medicina/Programa de Medicina Regenerativa, Universidad do Algarve (Portugal).
authors.forename: Gustavo
authors.initials: G
authors.lastname: Tiscornia
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503 (Japan).
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.affiliation: Sanin Rosai Hospital, Yonago 683-8605 (Japan).
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, Tokyo 204-8588 (Japan).
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503 (Japan). kh4060@med.tottori-u.ac.jp.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Instituto de Investigaciones Químicas (IIQ), CSIC-Universidad de Sevilla, Américo Vespucio 49, 41092 Sevilla (Spain). jogarcia@iiq.csic.es.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Garcia Fernández
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla c/Profesor García González 1, 41011 Sevilla (Spain). mellet@us.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D050505:Mutant Proteins; D054852:Small Molecule Libraries; D006026:Glycoside Hydrolases
keywords: chaperones; glycosidases; inhibitors; pH sensitivity; protein folding