title: (5aR)-5a-C-Pentyl-4-epi-isofagomine: A powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B.
abstract: This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal β-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human β-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC50= 8 nM, 30× more potent than 4-epi-isofagomine at pH 7.3) with a high selectivity for this glycosidase whereas the (5aS) epimer was a much weaker inhibitor. In addition, compound 1 showed a remarkable activity as a PC. It significantly enhanced the residual activity of mutant β-galactosidase in 15 patient cell lines out of 23, with enhancement factors greater than 3.5 in 10 cell lines and activity restoration up to 91% of normal. Altogether, these results indicated that (5aR)-5a-C-pentyl-4-epi-isofagomine constitutes a promising PC-based drug candidate for the treatment of GM1-gangliosidosis and Morquio disease type B.
authors.affiliation: Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Front
authors.affiliation: Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Biela-Banaś
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.
authors.forename: Patricie
authors.initials: P
authors.lastname: Burda
authors.affiliation: Center for Molecular Diseases, Lausanne University Hospital, 1005 Lausanne, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Ballhausen
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Neuroscience, Psychology, Pharmacology and Child Health Department, University of Florence, 50139 Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caciotti
authors.affiliation: Neuroscience, Psychology, Pharmacology and Child Health Department, University of Florence, 50139 Florence, Italy; Molecular and Cell Biology Laboratory, Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
authors.affiliation: Dorphan, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Charollais-Thoenig
authors.affiliation: Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Gallienne
authors.affiliation: Dorphan, EPFL Innovation Park, 1015 Lausanne, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Demotz
authors.affiliation: Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France. Electronic address: olivier.martin@univ-orleans.fr.
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Martin
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D016537:Gangliosidosis, GM1 / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D050112:Imino Pyranoses / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes / Q000201:enzymology*; D009085:Mucopolysaccharidosis IV / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011489:Protein Denaturation; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C000614378:(5aR)-5a-C-pentyl-4-epi-isofagomine; D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; C098432:isofagomine; D001616:beta-Galactosidase
keywords: GM1-gangliosidosis; Galactosidase inhibitors; Iminosugars; Morquio disease type B; Pharmacological chaperones