From temples to patios for carbohydrate recognition - expanding the scope of synthetic lectins.

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The selective binding of one molecule by another is a fundamental process in biology, central to the workings of life. There is great interest in mimicking this phenomenon for two reasons. Firstly, by studying synthetic systems we can throw light on their natural counterparts and test our understanding of the underlying principles. Secondly, if our systems can come close to their natural counterparts, they may serve useful functions in biology or medicine. This is a challenging goal, as proteins and nucleic acids are extraordinarily competent and difficult to match. However synthetic systems, if sufficiently effective, could have key advantages. They are likely to be more stable than biomolecules, and obtainable reproducibly in high purity. They are likely to be smaller than biomolecules, and therefore easier to study and characterise. They can also be modified with full structural control and essentially no design limitations.Carbohydrates are important targets for this type of research. On the one hand the binding of complex carbohydrate structures (oligosaccharides) by proteins (lectins) is known to regulate many natural processes. Molecules which mimic lectins could have a range of applications, both in research and medicine. On the other hand the principles which govern carbohydrate binding are not well understood, so there is special interest in developing synthetic models for the phenomenon. An underlying problem is that binding carbohydrates from water is intrinsically difficult. Superficially, carbohydrates are quite similar to clusters of water molecules, and it is challenging for a receptor (natural or synthetic) to distinguish one from other.Despite these difficulties, the PI's group have recently succeeded in designing some surprisingly effective synthetic lectins . These molecules bind carbohydrates under natural conditions with good affinities, and selectivities which in some senses are superior to natural lectins. However, to date their scope is limited; their temple architecture is only compatible with a narrow range of carbohydrates characterised by all-equatorial substitution patterns. Although this includes some important substrates (e.g. glucose), many applications lie out of reach. This project aims to broaden the scope of synthetic lectins by investigating a new receptor architecture, which we term the patio . The design is related to the successful temples but is modified so that it can accommodate axial substituents in the carbohydrate. Many variants are possible and it is likely that the approach could lead to a range of synthetic lectins with complementary selectivities. If they perform as well as we hope, these molecules could be used as research tools for biologists investigating the role of carbohydrates in nature, as agents for diagnosing diseases and possibly, after further development, as pharmaceuticals with a completely novel mode of action.