Professor B.G. Davis

Chemistry Research Laboratory

Email Address: Ben.Davis@chem.ox.ac.uk

Telephone: 44 (0) 1865 275 652

Research Interests

Our research comes under the broad headings of carbohydrate and protein chemical biology. The reactions and manipulation of sugars have fascinated organic chemists for over a century and this work is culminating today in a host of new drugs for treating disease. [1] The biological roles of carbohydrates have until relatively recently been viewed as simple ones: as sources of energy, e.g., glucose, or as polymeric building materials, e.g., chitin in crab shells, cellulose in wood. However, it is becoming increasingly clear that oligosaccharides, carbohydrates in small clusters, act as markers in important recognition processes such as microbial infection, cancer metastasis and cellular adhesion in inflammation, in addition to many intracellular communication events. [2] Their remarkable structural diversity means that oligosaccharides can mediate highly specific and therefore complex processes.[3]

The synthesis, manipulation and redesign of naturally occurring carbohydrate-containing structures allows the probing of key biochemical mechanisms and hence, through the understanding of these processes, the development of potential therapeutic strategies.[4] Our work involves experimental techniques ranging from novel synthetic methodology, target synthesis using both biotransformations and conventional synthetic methods to molecular modelling, enzyme kinetics and protein chemistry. This research explores the exciting and rapidly expanding interface between chemistry and biology. For full, constantly updated details of work in the group CLICK HERE.

(i) Novel Approaches to Glycoprotein and Glycoconjugate Synthesis:

It is hard to overestimate the importance of glycoproteins as signalling molecules in Nature. We have developed the first methods for site-selective protein glycosylation and therefore for accurate glycoprotein synthesis.[5] This has allowed, for example, the first precise determinations of the effects of glycosylation upon activity.[6] The power of this methodology is broad and has allowed us to create recently a remarkable new class of glycoconjugate: the glycodendriprotein, which can mimic natural glycoproteins in a completely novel antibacterial strategy.[7]

(ii) Synthesis using Novel Enzyme Systems:

Biocatalysis, the use of enzymes in synthesis, is an exciting field that allows the construction of complex and remarkable target molecules by exploiting the abundance of cataysis that Nature has to offer.[8] We have a broad interest in a host of enzymes: glycosyltransferases, glycosidases, proteases, lipases, acylases that we not only isolate from natural sources but that we also engineer for enhanced synthetic utility.
Excitingly, this allows us to probe the fundamentals of enyzme catalysis and to learn from the glorious architectures that Nature creates. For example, due to the difficulties of oligosaccharide and glycoconjugate synthesis there is presently a need for simple, easy-to-handle enzyme systems that will perform these reactions. To this end we have identified, isolated, engineered and modified proteases and glycosidases that will perform unusual reactions such as beta-mannoside formation, the ligation of non-coded[9] and D-amino acids[10] and the creation of exciting sugar-peptide and sugar-antibiotic conjugates.[11] These catalysts can be used to create new enzyme systems, glycopeptiligases,[11b] that can be used in our glycoprotein work to slot together glycopeptides, or to enhance the power of antibiotics by changing their sugar antennae.[11c]

(iii) Glycosylation Methodology:

Despite the best efforts of 140 years worth of chemists, a general method for the selective formation of oligosaccharides has still not been found.[12] We are exploring and have developed highly novel methods for controlling the reactivity, selectivity and specificity of oligosaccharide formation.[13] including solid-supported methods.

(iv) Novel Drug Delivery Systems:

The need to convert promising biologically-active molecules to effective therapeutic agents as rapidly as possible is driven by the limited length of proprietary protection and more urgently by the importance of more immediate treatment of life-threatening and debilitating diseases. Recent studies have highlighted the utility of targetted delivery as a more effective alternative to traditional methods. We are interested in novel, multicomponent and targetted approaches to drug delivery that involves the synthesis of modified macromolecule conjugates e.g., glyco-proteins, in conjunction with the design and synthesis of sugar-based drugs.[14] This has already allowed model treatment of certain cancers[14a] and if successful, will lead to lower drug doses and reduced adverse side effects. Other projects conducted in collaboration with Dr Neil Cameron, University of Durham and Dr. Alberto Smith, St. Thomas Hospital, London are investigating the potential of novel polymeric systems in targetted delivery and the fundamental relationship between precise control of delivery system structure and efficacy. This has, for example, allowed us to prolong the lifetime of sperm cells.[14b]

(v) Glycoprocessing Enzyme Inhibitors:

The specific inhibition of the enzymes that use sugars as their substrates (e.g., glycosidases and glycosyltransferases) provides valuable mechanistic information about their mode of action and is a therapeutic strategy for the treatment of disease. We are particularly interested in the design and synthesis of a novel inhibitors of glycosyltransferases, which are especially poorly studied enzymes. Such inhibitors represent potential therapeutic agents for the treatment of various diseases such as tuberculosis and arthritis. Recently, new multicomponent reactions have allowed the creation of the largest known libraries of so-called 'aza-' or 'imino-sugars' from which we were able to select new inhibitors effective against models of hepatitis-C virus.[15]

(vi) Solid Supported Methodology:

Although there is often a temptation to see solid-phase synthetic (SPS) methods as a separate discipline, we believe strongly that it is truly an additional, valuable tool to be expolited in all areas. To this end we have a keen interest in incorporating and exploiting such methods in all our work ranging from examples of solid-phase glycosylation technology[13a] to novel support assay methods.[16]

(vii) Asymmetric Methodology:

Carbohydrates are an unrivalled source of contiguous, stereogenic centres - chirality that grows on trees. It is therefore all the more surprising that their use to induce asymmetry has been more limited than the use of other sources. We are trying to change this by developing ligands and organocatalysts based on sugar scaffolds[17] and by exploring the role of sugars in prebiotic emergence of chirality. Already we have seen some striking levels of asymmetry[17b] in these systems that may be correlated with structural properties in the inducing scaffold, perhaps allowing access to 'programmed' induction.[17a]

References and Selected Publications:

1. K.J. Doores, D.P. Gamblin, B.G. Davis, Chem. Eur. J. 2006, 656-665.
2. (a) A. Varki, Glycobiol. 1993, 3, 97-130. (b) R.A. Dwek, Chem. Rev. 1996, 96, 683-720.
3. B.G. Davis, Chem. Ind. 2000, 134-138.
4. B.G. Davis, J. Chem. Soc. Perkin Trans. 1 1999, 3215-3237.
5. (a) B.G. Davis and J. Bryan Jones, Synlett 1999, 1495-1507. (b) D.P. Gamblin et al Angew. Chem. Intl Ed. 2004, 828-833.
6. B.G. Davis, R.C. Lloyd and J.B. Jones, Bioorg. Med. Chem. 2000, 8, 1527-1535.
7. (a) B.G. Davis, Chem. Commun. 2001, 351-352. (b) P.M. Rendle et al J. Am. Chem. Soc. 2004, 4750-4751.
8. B.G. Davis and V. Boyer, Natural Prod. Rep. 2001, 618-640.
9. K. Khumatveeporn, A. Ullman, K. Matsumoto, B.G. Davis and J.B. Jones, Tetrahedron: Asymm. 2001, 12, 249-261.
10. K. Matsumoto, B.G. Davis and J.B. Jones, Chem. Commun. 2001, 903-904.
11. (a) V. Boyer et al Chem. Commun. 2001, 1908-1910. (b) K.J. Doores, B.G. Davis, Chem. Commun. 2005, 168-170. (c) M. Yang et al J. Am. Chem. Soc. 2005, 9336-9337.
12. B.G. Davis, J. Chem. Soc. Perkin Trans. 1 2000, 2137-2160.
13. (a) B.G. Davis, S.J. Ward and P.M. Rendle, Chem. Commun. 2001, 189-190. (b) R.J. Tennant-Eyles et al Chem. Commun. 1999, 1037-1038. (c) E.J. Grayson et al J. Org. Chem. 2005, 9740-9754.
14. (a) M.A. Robinson et al Proc. Natl. Acad. Sci. USA 2004, 14527-14532. (b) C. Fleming et al Nat. Chem. Biol. 2005, 270-274.
15. T.M. Chapman et al J. Am. Chem. Soc. 2005, 506-507.
16. (a) J.P.S. Badyal et al Tetrahedron Lett. 2001, 8531-8533. (b) J.P.S. Badyal et al Chem. Commun. 2004, 1402-1403.
17. (a) D.P.G. Emmerson et al Org. Biomol. Chem. 2003, 3826-3838. (b) D.P.G. Emmerson, W.P. Hems, B.G. Davis Org. Lett. 2006, 207-210.

For a list of recent publications from the group see our group web pages.