Adamantyl globotriaosyl ceramide: a monovalent soluble mimic which inhibits verotoxin binding to its glycolipid receptor.
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.
Mylvaganam
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Division of Immunity, Infection, Injury and Repair Research Institute, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
Lingwood
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CA
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
D001427:Bacterial Toxins; D006017:Glycolipids; D011956:Receptors, Cell Surface; D022622:Shiga Toxin 1; D014281:Trihexosylceramides; D014867:Water; C018549:globotriaosylceramide; D000218:Adamantane