Project: Research project

Project Details


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.
Effective start/end date1/1/906/30/95