Chemistry, Chemical Biology and Biotechnology of Carbohydrates and Proteins.

Our research centres on the chemical understanding and exploitation of biomolecular function, especially carbohydrates and proteins. Interests and methods encompass organic synthesis & methodology, target biomolecule synthesis, inhibitor/probe/substrate design, biocatalysis, enzyme & biomolecule mechanism, biosynthetic pathway determination, protein engineering, drug delivery, molecular biology, structural biology, cell biology, molecular imaging and in vivo biology. 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.

The biological roles of carbohydrates have often 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. Their remarkable structural diversity means that oligosaccharides can mediate highly specific and therefore complex processes.

The central roles of proteins in biology have long been appreciated, yet their precise manipulation and redesign is still a vastly uncharted area for exploration. Novel chemical approaches have the potential not only to inform our understanding of their modes of action but will also allow us to redesign structure in line with intended function.

Current (often exclusively biological) methods for the manipulation of these pivotal ‘workhorse’ molecules of biology rely largely upon indirect manipulation of the DNA that encodes for relevant direct and indirect gene products. Frustrated by the limited molecular tools available to unpick the molecular mechanism of Biology, we have been working to circumvent this, the 'central dogma’ of molecular biology, to develop generally applicable, precise chemical manipulation and interrogation of structure and hence function at the level of the biomolecule (protein and carbohydrate).

The products of these new methodologies have the potential to reveal the mechanism of biology in a near-unlimited manner. This direct post-expression manipulation has the potential to uniquely expand and complement current methods used to probe Biology, which are used prior to expression. The full range of almost-unlimited chemical functionality can, in this way, be brought to bear in a biological context allowing, e.g., the site-selective reprogramming of the side-chain functional groups of proteins and carbohydrates without the need for intervening genetic manipulation. The building of biological constructs with selective chemistries and the use of their products to solve biological questions are now new fields referred to as Synthetic Biology and Chemical Biology, respectively.

• Biomolecule & Bioconjugate Construction: The invention of selective, biologically-compatible, bond-forming methodology to synthesize complex molecular & multi-molecular biological structures.
• Biomolecules & Bioconjugates as Probes of Mechanism in Biology:These synthetic methods have allowed creation of previously unavailable or unnatural biomolecules to precisely test molecular, mechanistic hypotheses in biology.
• Exploitation of Biomolecules & Bioconjugates in Medicine & Biotechnology:These probes have revealed mechanism and become tools that enable diagnosis, monitoring and treatment of disease.

These research interests are accomplished using the following interlinked technical themes:

• Chemistry for Biology:| Peptide, Protein, Oligosaccharide Synthesis | Natural Product Synthesis | Synthetic Methodology in Water | Chemical Proteomics |
• Biology for Chemistry:| Biocatalysis | Carbohydrate-Induced Asymmetry | Non-petroleum Feedstock Synthesis | Bioenergy and Biosequestration |
• Exploring, Exploiting and Designing Proteins:| Protein-Protein, Ligand-Protein, Enzyme-Substrate, Enzyme-Inhibitor Interactions |
• Synthetic Biology:| Top-Down | Bottom-Up | Post-translational Modification/Middle-Out |
• Post-translational Modifications:| Synthetic Proteins | Chemical Circumvention of Genetics | Synthetic Biology |
• New Tools for Chemical Medicine:| Imaging | Delivery | Treatment |

This work is or has been supported by the EPSRC, the BBSRC, the MRC, The Gates Foundation, The Wellcome Trust, the Morningside Foundation Cancer Research UK, the Royal Society, UCB-Celltech, the EU, Glycovaxyn, Pfizer, AstraZeneca, GlaxoSmithKline, Lab282, Evotec, and Novartis.