Kurzbeschreibung
(Englisch)
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The present project is aimed at the synthesis of efficient and selective Cholera Toxin (CT) inhibitors to be used in clinical studies and in sensing devices. The synthesis of efficient multivalent mimics of the natural ligand, the oligosaccharides o-GM1 hybridized with corannulene as a five-fold symmetric core, will be pursued. The quality of the mimics' design will be tested using NMR spectroscopy and molecular modelling studies to determine the structural similarity (including conformations) between the newly designed molecules and GM1. Different spacers, binding groups, valency and conformational mobility of the scaffold will be encorporated into the design. The complexes between all the synthesised multivalent ligands of CT will be structurally characterised and their stability evaluated using different complementary techniques such as fluorescence, SPR and ELISA tests. High-affinity ligands for CT will possibly lead to candidate drugs able to block the interaction of the toxin with the target cells, thus preventing the onset of the disease. Some of the strongest inhibitors will be also anchored on solid supports (silicon or gold) to develop sensors for Cholera Toxin. Throught he COST collaboration, new diagnostic ELISA's tests for the direct identification of LOS-induced antibody responses in various groups of Guillain-Barré Syndrome affected patients will be developed.
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Partner und Internationale Organisationen
(Englisch)
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AT, BE, CH, CZ, DE, ES, FR, GR, IE, IL, IT, LT, LV, NL, NO, PL, PT, SI, SK, UK
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Abstract
(Englisch)
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The present project is aimed at the synthesis of efficient and selective Cholera Toxin (CT) inhibitors to be used in clinical studies and in sensing devices. The synthesis of efficient monovalent mimics of the natural ligand, the oligosaccharides o-GM1 were pursued as outlined in our proposal. A few selected mimic candidates were prepared with an anchoring group and then conjugated to the multivalent scaffols of corannulene. The synthetic complexes were chemically characterized by NMR and MS techniques. Despite the successful synthesis of the chemically designed agents, evaluation of their interactions with Cholera toxin were inhibited by issues of the agent’s solubility in the media of the test. Compounds were tested in house, but also in Milan, Copenhagen and London through our COST network. Their stability evaluated using different complementary techniques such as fluorescence, SPR, ITC and ELISA tests gave uniformly ambiguous results. This required us to develop a new design and chemical synthesis, which is presently underway via two strategies: 1) Change linker to impart solubility and 2) Achieve greater control over substituents around the rim.
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