BLOCKAGE OF TOXIN-CELL INTERACTIONS BY OLIGOSACCHARIDES

我们的目标是设计一个一般协议的发展抑制剂 细菌毒素与其靶细胞表面的结合 鞘糖脂受体 如果毒素与细胞的相互作用被阻断， 应防止毒素引起的有害影响 约束力 肉毒梭菌神经毒素的亲和性 (type E）和破伤风梭菌对其推定的神经节苷脂受体的作用 将被确定，以确定哪种G1 b神经节苷脂 系列是各自的优选受体。 的寡糖部分， 破伤风和肉毒杆菌毒素的受体加上GM 1的受体 （霍乱弧菌肠毒素的受体）将被分离，使用 简单而直接的程序，在这个实验室开发，并使用 在开发载体连接的低聚糖方面， 结合位点定向的不可逆抑制剂。 的合成方案 提出的用于合成载体连接的寡糖的方法应 导致形成可能类似于 当毒素与其细胞表面相互作用时， 受体的 将检测载体连接寡糖的 抑制毒素-细胞相互作用的能力。 最后， 低聚糖将使用N.M.R.测定。光谱和 用于开发毒素-受体相互作用的模型。 这些信息应作为制定 位点特异性寡糖抑制剂，毒素将具有这种 毒素-寡糖相互作用的高亲和力 基本上是不可逆的。

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.