Research Guides

Research Interests 

Our research comes under the broad heading of the chemistry of Carbohydrates and Proteins. The reactions and manipulation of sugars and proteins have fascinated organic chemists for over a century and this work is culminating today in a host of new drugs for treating diseases. It is becoming increasingly clear that oligosaccharides (carbohydrates in small clusters)[1]  and alterations in proteins (modifications)[2]  are examples of chemically complex biological markers that can act in important recognition processes such as microbial infection, cancer metastasis and cellular adhesion in inflammation, in addition to many intracellular communication events. Their remarkable structural diversity means that they can often mediate highly specific and therefore complex processes.

Our work comes under the broad headings of the Chemistry, Chemical Biology and Biotechnology of Carbohydrates and Proteins. Interests encompass organic synthesis and methodology, inhibitor design, biocatalysis, enzyme mechanism, protein engineering, drug delivery, molecular modelling, molecular biology, imaging and translation into in vivo systems. The application of an understanding of such systems on a fundamental level leads to the design, synthesis and modification of potential therapeutic and biotechnologically applicable systems.[3]

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.
 

This work is grouped into the following interlinked themes:

One may compare Synthetic Biology's development at the start of this century with Synthetic Organic Chemistry's expansion at the start of the last: after decades of isolation, identification, structural analysis and functional confirmation, the future logical and free-ranging redesign of biomacromolecules offers tantalizing opportunities. New methods and strategies are required. Alternative strategic starting points (top, middle and bottom) provide alternative perspectives and complementary approaches. In this area we explore:

Synthetic Protein Design and Assembly: Middle-Out Synthetic Biology & PTMs - Nature achieves breathtaking structural and functional diversity through the process of protein alteration, yet as chemists we have been slow to follow this informative lead. Despite 80-years-worth of non-specific, chemical modification of proteins, precise methods in protein chemistry remain rare. The development of efficient, complete, chemo- and regio-selective methods, applied in benign aqueous systems to redesign the structure and function of proteins is one of our primary interests. Invention and use of dual tag-modify strategy has allowed us to build synthetic proteins[4] that, for example, function as effective mimics both in vitro and in vivo. We have used these to map cognate binding partners in mammalian brain.[5]

Towards the Chemical Cell (CHELL): Bottom-Up Synthetic Biology - The potential assembly of simple building blocks into cell-like and life-like constructs continues to act as an iconic goal for those interested in understanding the pre-biotic chemical processes that may have given rise to life. These studies may inform on the origins of the sugars and amino acids that led to life, challenge current notions on how life-like processes may be assembled and even stimulate debate on what might be considered to be life. We explore novel approaches to creating chemical cell-like entities (CHELLs, CHemical cELLs)[6] that may be used to test principles and to explore interactions with natural cells.[7]

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 visualization of disease and delivery as a more effective alternatives to traditional methods. In this area we explore:

Delivery - We are interested in novel, multicomponent and targeted approaches to drug delivery that involves the synthesis of modified macromolecule conjugates e.g., glycoproteins, in conjunction with the design and synthesis of sugar-based drugs. This strategy has led to the development of the "LEAPT" drug delivery system[8] and glycoviruses for targeted delivery in gene therapy.[9] These principles of sugar-targeting have been extended to libraries of glycopolymeric prodrugs that have been used, for example, to extend the lifetime of sperm through targeted antioxidant delivery.[10]

Imaging and Probing - We have developed methods for accessing a wide range of conjugates as tools for in vivo imaging, probing and manipulation.[3]] This work is based on an understanding of the key processes on a structural level and the use of those principles to develop targeted, functional and responsive molecular medicine strategies. This work includes drug and gene delivery, synthetic protein assembly and smart agents for imaging. Examples of bioconjugate tools include re-tuned viruses [9], carbon nanotubes [11],[25] functional MRI particles for detecting brain disease[12] and single-molecule sensors of pathogens and toxins.

Peptide and Protein Synthesis - Peptide synthesis technology is well-advanced and allows the routine assembly of simple peptides up to 30 residues on scale and with good fidelity. However modified peptides or those of greater length often demand novel approaches. As well as making use of all modern peptide synthesis technology (including solid-phase, solution-phase, microwave assisted) we have also developed strategies for the synthetic linear assembly of full length proteins. For example, recent work[13] has made use of redesigned peptide ligation catalysts without the need for protecting groups to create probes of MHC class II processing[14]

Glycoside and Oligosaccharide Synthesis - Despite the best efforts of 140 years worth of chemists, a general method for the selective formation of oligosaccharides has still not been found. Although some of the established glycosylation methodologies lend themselves to potential automation a truly general method for glycosylation is still one of the great unsolved challenges in organic chemistry.[15] As well as employing more-traditional methods for synthesizing a wide variety of biologically relevant oligosaccharides, we are exploring the judicious use of both chemistry and biology to try and simplify and enhance current approaches and generate new strategies.

Natural Product Synthesis - As the products of evolved interactions natural products may offer unique biological activities, often with exquisite selectivity and activity. Through their target synthesis,[16] we explore the use of small natural products and the design of analogues with altered or enhanced properties for use in biology.

New Reactions in Water - At the heart of our work is the development of synthetic methodology for chemoselective and regioselective manipulation of protein structure. These macromolecules are challenging and exciting starting materials for synthesis that must be manipulated with minimal protecting group strategy, so often relied upon in synthesis. This necessitates novel strategies, reagents and catalysts.[17]

Biocatalysis: Exploring Enzyme Systems for use in Synthesis - We have a keen interest in the function and use of enzymes. Not only can their use in synthesis often allow reactions to be performed in a much more convenient way but their mechanisms and mode of action provide a wonderful insight into novel chemistries. Much of our work focuses on the use of enzymes in the formation of sugars and their mimics. We are engaged in the isolation of some powerful new examples of the catalysts that nature uses to put sugars together. This has led to the development of novel screening strategies that may be applied to all enzyme classes.[18] Use of this powerful system has allowed us to dissect the mechanism and kinetics of glycosyltransferases.[19] and the discovery and engineering of other synthetic carbohydrate biocatalysts.[20] Some of these glycosyltransferases have been used, for example, to remodel antibiotics to create non-natural variants with higher efficacy.[19]

Carbohydrate Induced Asymmetry - Carbohydrates are powerful sources of chirality for use in synthetic asymmetric processes and often prove to be superior to more simple sources. Despite such clear indications, systematic structure-function relationships of carbohydrate ligands, reagents or catalysts are rare. This seems all the more remarkable given that they are a prime source of contiguous, stereogenic centres that may be readily manipulated both in configuration and functionality to allow rapid fine tuning of their function. We explore the use of sugars to induce asymmetry, particularly in 1,2-additions to carbonyls,[21] attaining promising selectivities that outstrip those of existing systems. Systematic configurational alteration of scaffolds has allowed us to conduct some of the most detailed structure-activity relationship (SAR) studies to date.[21a] Recent work is developing carbohydrate-based organocatalysts.

Non-petroleum Feedstock Synthesis - Glucose is the most abundant organic moiety on the plant. Current estimates of oil supplies will allow only 20-30 years of our current petroleum-based synthetic strategies. Taught and adopted strategies have ironically moved away from chiral pool to simple oil-based building blocks, which while allowing conceptually elegant elaborations rely heavily on dwindling resource. We explore new strategies (starting largely from sugars) and the re-birth of chiral pool/chiron methods that focus on biological origin, sustainable availability and true 'atom economy' (ie taking the energy that is supplied from the sun as the primary determinant of chemical strategy - "chemistry that grows on trees").

Protein-Protein Interactions - The redesign of proteins based on an insight into their assembly and into the structural features that mediate protein-protein interfaces has allowed us to better understand and exploit these processes. Redesign of a plant lectin allowed us to develop a system of redox-switchable agglutination for red blood cell sensing[22]. Recently synthetic mimics of PTM-proteins have allowed us to develop in vivo probes of disease based on PTM-mediated protein-protein binding.[5]

Protein-Ligand and Enzyme-Substrate Interactions - An interest in fundamental enzymology and binding processes of many proteins has led to the development of novel screening strategies that may be applied to many protein and all enzyme classes.[18] For example, use of a powerful MS-based system has allowed us to dissect the mechanism and kinetics of glycosyltransferases. Our work with Prof John Simons is allowing us to probe the inherent conformational bias of glycans free from solvent in the gas phase.[23] This work is highlighting clear parallels with binding modes of many protein ligands and allowing the development of models of carbohydrate secondary structure. It has also recenly led to the first 'unclouded' measurement of the anomeric effect.[26]

Enzyme-Inhibitor Interactions - The specific inhibition of the enzymes that use sugars as their substrates (glycosidases and glycosyltransferases) provides valuable mechanistic information about their mode of action and is a therapeutic strategy for the treatment of disease. We have developed new methods for rapidly elaborating heterocyclic scaffolds to create diverse libraries of glycoprocessing enzyme inhibitors.[24] From these we can identify candidates for the treatment of diseases such as Gaucher's disease or Hepatitis C. We are also interested in the design and synthesis of transition-state analogue inhibitors of glycosyltransferases, which are especially poorly studied enzymes. Such inhibitors represent potential therapeutic agents for the treatment of tuberculosis, inflammatory diseases such as arthritis, cancer and lysosomal storage diseases. We combine this synthetic work closely with an enzymological approach to the redesign of enzyme function through mutagenesis, forced evolution and structural characterization to further our understanding of such systems. Some of these compounds are low toxicity, cell permeable agents with promising anti-viral activities. Our ongoing programme in this area is exploring their potential in chemical genetic control of intracellular glycan processing and as tools in cell biology.

Understanding Biological Diversity - The apparent lack of correlation between the number of genes in an organism and its resulting biological complexity raises interesting and fundamental issues in biology. One possible source of our complexity is post-translational modification (PTM): the alteration of proteins after translation, typically through changes to their amino acid side chains. However, the processes that give rise to PTMs are complex and not template driven and often give rise to product mixtures. The result is that dissecting the effect of PTMs on protein function is challenging. We have proposed[2] that one strategy for dissecting the structure-activity relationships of PTMs might be through the use of chemistry, through the construction of synthetic proteins containing PTMs or PTM-mimics. We have developed new tools[4] that rely upon a "tag-modify" approach to introduce a wide range of modifications including glycosylation, sulfation, phosphorylation and methylation under the control simply of chemistry not biology. This work is now developing into broad strategies for accessing, through chemistry, proteins that have precisely altered residue structure. Chemical switching in proteins is allowing us to move towards the goal of "chemical mutagenesis".

Chemical Genetics & Selective Chemical Intervention in Biological Systems (SCIBS) - Multicomponent & array chemistry[24] has allowed us to assemble libraries of cell-permeable compounds that can modulate, interrupt and augment the processes that control protein modification. This strategy of is of particular relevance to PTM control in the absence of ready methods for genetic or RNAi control.

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2. B.G. Davis, Science 2004, 303, 480-482.
3. K.J. Doores, D.P. Gamblin, B.G. Davis, Chem. Eur. J. 2006, 656-665.
4. B.G. Davis, Pure Appl. Chem.2009, 81, 285-298 1495-1507.
5. S.I. van Kasteren et al Nature 2007, 446, 1105-1109.
6. L. Cronin et al Nat. Biotechnol. 2006, 24, 1203-1206.
7. P.M. Gardner, K. Winzer, B.G. Davis, Nat. Chem. 2009, 1, 377-383.
8. M.A. Robinson et al Proc. Natl. Acad. Sci. USA 2004, 101, 14527-14532.
9. O.M.T. Pearce et al Angew. Chem. Int. Ed. 2005, 44, 1057-1061.
10. C. Fleming et al Nat. Chem. Biol. 2005, 1, 270-274.
11. S.Y. Hong et al J. Am. Chem. Soc. 2007, 129, 10966-10967.
12. S.I. van Kasteren et al Proc. Natl Acad. Sci. U.S.A. 2009, 106, 18-23.
13. K.J. Doores, B.G. Davis, Chem. Commun. 2005, 168-170.
14. Y. Mimura et al Proc. Natl Acad. Sci. U.S.A. 2007, 104, 5983-5988.
15. B.G. Davis J. Chem. Soc., Perkin Trans. 2000, 2137-2160.
16. M.A.T. Maughan, I.G. Davies, T.D.W. Claridge, S. Courtney, P. Hay, B.G. Davis Angew. Chem. Int. Ed. 2003, 42, 3788-3792.
17. (a) Y.A. Lin et al J. Am. Chem. Soc. 2008, 130, 9642-9643. (b) J.M. Chalker et al J. Am. Chem. Soc. 2009, 131, 16346-16347.
18. M. Yang, M. Brazier, R. Edwards, B.G. Davis ChemBioChem 2005, 6, 346-357.
19. M. Yang, M.R. Proctor, D.N. Bolam, J.C. Errey, R.A. Field, H.J. Gilbert, B.G. Davis J. Am. Chem. Soc. 2005, 127, 9336-9337.
20. M. Yang, G.J. Davies, B.G. Davis Angew. Chem. Int. Ed. 2007, 46, 3885-3888.
21. (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.
22. R.E. McDonald, D.J. Hughes, B.G. Davis Angew. Chem. Int. Ed. 2004, 43, 3025-3029.
23. E.C. Stanca-Kaposta et al J. Am. Chem. Soc. 2008, 130, 10691-10696.
24. T.M. Chapman et al J. Am. Chem. Soc. 2005, 506-507.
25. S.Y. Hong et al Nature Materials 2010, 9, 485-490.
26. E. Cocinero et al Nature 2011, 469, 76-79.