title: Adamantyl globotriaosyl ceramide: a monovalent soluble mimic which inhibits verotoxin binding to its glycolipid receptor.
abstract: The globotriaosylceramide (Gb3) verotoxin (VT) interaction is one of several examples of glycolipid receptors where the ceramide (or lipid) free oligosaccharides fail to show the expected binding parameters. We present a novel, yet simple strategy to synthesize monovalent, water soluble glycosphingolipid mimics which retain receptor function. Replacing the fatty acid chain with rigid, three dimensional hydrocarbon frames, such as adamantane, gives a novel class of neohydrocarbon glycoconjugates. Such adamantyl conjugates derived from Gb3 showed significantly enhanced solubility in water compared to natural Gb3. Adamantyl-Gb3 showed a thousand fold enhanced inhibitory activity (IC50 = 1 microM) for VT-Gb3 binding as compared to a lipid free Gb3 oligosaccharide derivative, alphaGal1-4betaGal1-4betaGlc1-O-CH2CH(CH2SO2C 4H9)2 (IC50 > 2 mM). This represents a new approach to the generation of antagonists of glycolipid receptors.
authors: Division of Immunity, Infection, Injury and Repair Research Institute, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
authors: M
authors: M
authors: Mylvaganam
authors: C A
authors: CA
authors: Lingwood
mesh_terms: D000218:Adamantane / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002855:Chromatography, Thin Layer; D015195:Drug Design; D006017:Glycolipids / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry; D018716:Molecular Mimicry; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D022622:Shiga Toxin 1; D012995:Solubility; D014281:Trihexosylceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014867:Water / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D006017:Glycolipids; D011956:Receptors, Cell Surface; D022622:Shiga Toxin 1; D014281:Trihexosylceramides; D014867:Water; C018549:globotriaosylceramide; D000218:Adamantane