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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Bacteriology and Mycology Subcommittee 1 (BM)
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Pennsylvania State University
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Thompson, J P; Schengrund, C L (1997) Oligosaccharide-derivatized dendrimers: defined multivalent inhibitors of the adherence of the cholera toxin B subunit and the heat labile enterotoxin of E. coli to GM1. Glycoconj J 14:837-45
Schengrund, C L; DasGupta, B R; Hughes, C A et al. (1996) Ganglioside-induced adherence of botulinum and tetanus neurotoxins to adducin. J Neurochem 66:2556-61
Schengrund, C L; DasGupta, B R; Ringler, N J (1993) Ganglioside GD3 enhances adherence of botulinum and tetanus neurotoxins to bovine brain synapsin I. Neurosci Lett 158:159-62
Schengrund, C L; Ringler, N J; Dasgupta, B R (1992) Adherence of botulinum and tetanus neurotoxins to synaptosomal proteins. Brain Res Bull 29:917-24
Schengrund, C L; DasGupta, B R; Ringler, N J (1991) Binding of botulinum and tetanus neurotoxins to ganglioside GT1b and derivatives thereof. J Neurochem 57:1024-32
Fueshko, S M; Schengrund, C L (1990) Murine neuroblastoma cells express ganglioside binding sites on their cell surface. J Neurochem 54:1791-7
Schengrund, C L (1990) The role(s) of gangliosides in neural differentiation and repair: a perspective. Brain Res Bull 24:131-41
Schengrund, C L; Ringler, N J (1989) Binding of Vibrio cholera toxin and the heat-labile enterotoxin of Escherichia coli to GM1, derivatives of GM1, and nonlipid oligosaccharide polyvalent ligands. J Biol Chem 264:13233-7
Schengrund, C L; Prouty, C (1988) Oligosaccharide portion of GM1 enhances process formation by S20Y neuroblastoma cells. J Neurochem 51:277-82
Schengrund, C L; Shochat, S J (1988) Gangliosides in neuroblastomas. Neurochem Pathol 8:189-202