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

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.

Who will benefit from this research? Beyond academia, the research has the potential to benefit chemical and biomedical researchers in industrial laboratories and in third sector institutions (e.g. medical research institutes). It could also have relevance to the general public and the economy. A PDRA will be trained through performing the research. How will they benefit from the research? The following benefits may be identified or envisaged. (a) The project will contribute to an improved understanding of molecular recognition, benefiting medicinal chemists and biochemists and thence the general public. A full understanding of molecular recognition, especially under biological conditions, has important implications for society. Many of the most valuable molecules produced by the chemical industry operate through binding selectively to other molecules, the obvious example being pharmaceuticals. Research which throws light on non-covalent binding provides the theoretical background to the design of these molecules. The proposed work will be especially informative as the binding of polar molecules under aqueous conditions is still not well-understood. Moreover, there is specific interest in the recognition of carbohydrates, which represent major targets for drug discovery. (b) Conceptually, the work will highlight the potential for rational molecular design, especially when inspired by biology. We believe this will appeal to an audience well beyond academic chemistry, extending to the scientifically literate general public. The use of chemical synthesis to create functional molecules (as in molecular engineering , molecular machines ) is an engaging topic which can be used to enhance the image of chemistry (as well as being a long-term technological objective). The emulation of nature adds to the interest. We have already shown that synthetic lectins can attract attention from non-specialists by reporting one of our systems in Science. This publication stimulated articles in general chemistry magazines (Chem and Eng News, Synform), and was featured on science news websites such as physorg.com (as well as the University of Bristol central website). (c) On a practical level, the synthetic lectins produced during the work could be used in the development of tools for glycobiological research, e.g. stains for carbohydrate moieties on cells or proteins, stationary phases for glycoprotein purification, or, in the longer term, arrays for glycomic analysis. These applications were discussed under Academic Beneficiaries , but are equally relevant to researchers in industry or medical institutes. (d) Ultimately, synthetic lectins could find use in medicine, both in diagnosis and in treatment. Diagnostic applications would emerge as extensions of the research tools described under (c) above. For example, synthetic lectin-based stains might be developed for tumour-associated carbohydrate antigens such as the TF or Tn antigen. Also, synthetic lectin microarrays could be used to help identify pathogens, based on glycosylation profiles. Pharmaceuticals based on synthetic lectins can also be envisaged. Cell and pathogen adhesion is often mediated by protein-carbohydrate interactions, and synthetic lectins could interfere with these processes leading, for example, to anti-infective, anti-metastatic or anti-inflammatory effects. Such applications are certainly not close, and would require long-term research efforts. Notably, it would be necessary to raise affinities substantially. However, exploiting multivalency to enhance binding may well provide a solution. Any applications in medicine could result in major economic benefits. (e) The PDRA will gain broad experience by working on a multidisciplinary project. He/she will become familiar with the biological background to the research while undertaking practical work in organic synthesis and the measurement aspects of supramolecular chemistry.