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. These rely on application of native chemical ligation and expressed protein ligation methods in addition to novel ligations based on disconnections that go beyond the established Wieland-Kent Gly-Cys linkage approach.

For example, biocatalytic strategies[pub 78] have made use of redesigned peptide ligation catalysts that for the first time allow direct assembly at modified linkages (e.g. glycoamino acid residue sites) without the need for protecting groups. The resulting modified peptides were used as probes of MHC class II processing[pub 84]

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.[pub 19]

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. These include solid supported methods,[pub 22] the use of unprotected glycosyl donors,[pub 34] and through a collaboration with Dr Antony Fairbanks we have explored novel methods for controlling the selectivity of oligosaccharide formation that involves tethering the reactants via a tailored conformationally-rigid bridges.[pub 40] Key examples have allowed us to construct fragments of functional oligosaccahrides in nature and, through synthesis, to develop models for their roles and modulation in biological assembly.[pub 138]

In addition, the use of carbohydrate biocatalysis features heavily in our approaches.

We have developed new classes of glycosyl donors[pub 22][pub 72] that may be tuned via their aglycon unit and readily used to create conjugatable oligosaccharide products.[pub 157]

Current key targets for this glycosylation methodology include pure N-linked glycoprotein glycans and heparan / heparin sulfate glycans and their corresponding non-natural variants for the elucidation of interactions with binding protein partners.[pub 193]

These syntheses are also allowing us to probe the inherent conformational bias of glycans free from solvent in the gas phase in collaboration with Prof John Simons, Dr Pierre Carcabal and Dr Emilio Cocinero.[pub 86][pub 150][pub 176][pub 182][pub 193]

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

Simple use of temperature as the controlling element (Control of Lone-Pair "Flipping") allowed us to develop a novel stereodynamic synthetic approach to elaborating scaffolds of imino sugars such as the classic inhibitor DNJ.[pub 44] Moreover through appropriate understanding of the stereoselectivity of the addition of nucleophiles to cyclic sugar imines we were able to complete the first total synthesis of the naturally-occurring carbohydrate mimetic, adenophorine.

As an alternative chemoenzymatic strategy, the synthetic use of enzymes involved in biosynthesis[pub 77][pub 83] has allowed and is allowing the remodelling, for example, of macrolide[pub 66] and other unusual[pub 143][pub 177] antibiotics to enhance their function.

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 [pub 85], novel reagents [pub 97], novel substrates [pub 100] and novel catalysts.[pub 129]