LECNAC · Synthetic lectins for beta-GlcNAc: evaluation of their potential biological applications towards O-GlcNAc-modified proteins

Synthetic lectins for beta-GlcNAc: evaluation of their potential biological applications towards O-GlcNAc-modified proteins

Lectins are carbohydrate-binding proteins which play many roles in nature, and are important also as tools for biomedical research. For example, they are used to make fluorescent reagents which bind to, and thus identify, particular carbohydrate units, and also to make separation media which distinguish between differently glycosylated biomolecules. An important target for such reagents / media is beta-GlcNAc on serine or threonine (the O-GlcNAc protein modification). This moiety has been implicated in many biological processes and human diseases such as diabetes and neurobiological disorders. Although lectins are the standard tools for selective binding of carbohydrates, they do not always perform especially well. The binding of GlcNAc provides an example - the lectin normally used for this target, wheat germ agglutinin (WGA) shows low affinities and only moderate specificity. Recently it has emerged that 'synthetic lectins' may provide a viable alternative. In particular, the host group has shown that a tricyclic cage compound can bind O-GlcNAc units with affinities which match that of WGA and considerably greater selectivity. The scientific aim of the project was to build on this achievement, and demonstrate that synthetic lectins could serve as genuinely useful tools for studying this important moiety. While the host group published system has potential for application as an O-GlcNAc receptor, it was clear that its moderate affinity (equivalent to WGA) would serve as a handicap. Design work in the early stages of the project suggested an alternative which could be far more effective, and it was decided to focus on this system. The synthesis of the proposed receptor has proved exceptionally challenging, mainly because of the insoluble nature of key components with condensed aromatic structures. However, by the end of the project the work was 95 % complete. It is currently being finished by another member of the group, and testing should commence soon. If the receptor behaves as expected, it could make a very significant contribution to research on the O-GlcNAc protein modification. By providing an improved alternative to WGA, it would also demonstrate that designed synthetic molecules can compete with natural counterparts in challenging areas of molecular recognition.

Data: CORDIS, © European Union