Specific binding between bacterial enterotoxins and oligosaccharides on the host cell membrane is a paradigm for protein-sugar interaction. One of the best-characterized recognition pairs is formed by ganglioside GM1 and the cholera toxin (CT).
Synthetically accessible ganglioside mimics that act as high-affinity ligands for CT may lead to drugs capable to block the interaction between the toxin and target cells, thus preventing the onset of the disease. Much synthetic effort has been devoted to the synthesis of gangliosides, but the development of ganglioside mimics is still surprisingly little explored.
The major part of the reports come from the host laboratory which has reported a group of pseudo-oligosaccharides, rationally designed to mimic the 3D structure of GM1. Some of these molecules display high affinity for CT and are structurally much simpler than the natural ligand, but their rather complex synthesis and expected instability towards glycosidases make them poor candidates for potential medicinal applications.
The present project is aimed to the design and synthesis of glycosidase stable mimics of the GM1 ganglioside as efficient and selective CT inhibitors. As a general strategy, the two-pharmacophoric fragments of GM1, a sialic acid and a galactose residue, will be connected to each other through a linker using non-glycosidic bonds.
The linkers' design will be based on the known X-ray structure of the CT: GM1 complex. Optimization of the linker will be obtained either through parallel synthesis or using a target-guided approach. This project is connected to the activities of the COST D34/001/05 WG, working on cholera toxin inhibition and sensing.
This fellowship and the framework provided by the COST group will ensure the opportunity for the pro poser to be exposed to an interdisciplinary context while working on a timely scientific project resulting from the coordinated efforts of internationally recognized research leaders in glycoscience.
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