BLOCKAGE OF TOXIN-CELL INTERACTIONS BY OLIGOSACCHARIDES

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Our aim is to devise a general protocol for the development of inhibitors of the binding of bacterial toxins to their target cell surface glycosphingolipid receptors. If the toxin-cell interaction is blocked, it should prevent the resultant deleterious effects induced by the toxin binding. The binding affinity of the neurotoxins of Clostridium botulinum (type E) and Clostridium tetani to their putative ganglioside receptors will be determined in order to ascertain which ganglioside of the G1b series is the preferred acceptor for each. The oligosaccharide portions of the receptors for the tetanus and botulinum toxin plus that of GM1 (receptor for the enterotoxin of Vibrio cholera) will be isolated, using a simple and straightforward procedure developed in this laboratory, and used in the development of carrier-linked oligosaccharides and binding-site-directed irreversible inhibitors. The synthetic scheme proposed for the synthesis of the carrier-linked oligosaccharides should result in the formation of clustered oligosaccharides possibly resembling those "seen" by the toxin when it interacts with its cell surface receptor. The carrier-linked oligosaccharides will be tested for their ability to inhibit toxin-cell interactions. Finally, the conformation of the oligosaccharides will be determined using n.m.r. spectroscopy and utilized in the development of models of the toxin-receptor interactions. This information should provide the basis for the development of site-specific oligosaccharide inhibitors for which the toxin will have such a high affinity that the toxin-oligosaccharide interaction will be essentially irreversible.