title: Glucosylceramide mimics: highly potent GCase inhibitors and selective pharmacological chaperones for mutations associated with types 1 and 2 Gaucher disease.
abstract: A series of iminoxylitol derivatives carrying a C-linked di-O-acyl or di-O-alkyl glyceryl substituent were prepared and characterized. All of these compounds, which were designed as glucosylceramide (GlcCer) mimics, were nanomolar inhibitors of lysosomal β-glucosidase (glucocerebrosidase, GCase). Two of these pseudoglycolipids were further evaluated for their ability to enhance the activity of mutant GCase in human Gaucher cells. Although the di-O-hexyl ether was surprisingly devoid of chaperoning activity on both N370S and L444P GCases, the di-O-decanoyl ester was a potent chaperone of the L444P hydrolase, capable of increasing the residual activity of the enzyme by a factor of two at a very low concentration (50 nM); such a significant effect on the L444P mutation in human fibroblasts has not yet been observed. In heat-stress studies, the diether was found to be much more effective in stabilizing the wild-type enzyme than the diester. Four representative pseudoglycolipids were also assayed as inhibitors of GlcCer synthase, because such compounds could find use in the substrate reduction therapy approach to treat lysosomal storage diseases, but these compounds revealed only moderate activity. As efficient pharmacological chaperones, new structures such as the di-C10 -ester constitute leads for the development of therapeutic agents for types 2 and 3 Gaucher disease, the most severe neuronopathic forms of this lysosomal disease.
authors.affiliation: Institute of Organic & Analytical Chemistry (ICOA), University of Orléans, CNRS-UMR7311, Rue de Chartres, 45067 Orléans (France); Faculty of Chemistry, Jagellonian University, Ingardena 3, 30-060 Krakow (Poland).
authors.forename: Wojciech
authors.initials: W
authors.lastname: Schönemann
authors.forename: Estelle
authors.initials: E
authors.lastname: Gallienne
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ikeda-Obatake
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.forename: Marcin
authors.initials: M
authors.lastname: Górecki
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Frelek
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Martin
mesh_terms: D032701:Biomimetics; D002240:Carbohydrate Sequence; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors*; D005963:Glucosylceramides / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry* / Q000494:pharmacology; D009154:Mutation
chemical_list: D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D018832:Molecular Chaperones; D005962:Glucosylceramidase
keywords: Gaucher disease; glycolipids; glycosidase inhibitors; iminosugars; pharmacological chaperones