OUR RESEARCH

The synthesis of complex oligosaccharide targets remains a cornerstone of glycoscience research and we have several projects ongoing in this area that are both fundamental in nature and linked to the industrial importance of carbohydrates.

Synthetic approaches to glycosaminoglycans

We are developing new synthetic methodologies and technologies to rapidly access complex glycosaminoglycan sequences. Currently, this includes:

• Both native and modified building blocks for GlcN, GalN, GlcA and IdoA containing oligosaccharide targets.
• Heparan and chondroitin sulfate oligosaccharide synthesis.
• Novel methodologies to enable oligosaccharide conjugations.

Synthetic approaches to alginates

We are also working on the synthesis of structurally-modified alginate oligosaccharides, including:

• Recently demonstrating the first examples of hydroxamate-modifed disaccharide building blocks (Org. Biomol. Chem., 2019).
• Structural modifications to probe alginate polysaccharide structure to function, in collaboration with Unilever.

ribose ring modifications

Nucleoside analogues are historically accomplished as medicinal agents for the treatment viruses and a wide variety of cancers.

Here we are developing syntheses of next generation nucleoside analogues for evaluation against viral and oncogenic targets. This work is being undertaken in collaboration with US Biotechnology company Riboscience LLC.

• Recently we demonstrated the replacement of furanosyl oxygen with 4′-thio and 4′-sulfinyl components for a range of pyrimidine nucleosides (Org. Biomol. Chem. 2022).

Sugar-nucleotides are imperative to carbohydrate metabolism and glycoconjugate biosynthesis. Accordingly, they are of considerable interest as carbohydrate-based tools for the study of glycoconjugate biosynthesis and for their potential as enzyme probes/inhibitors to new therapeutic strategies.

GDP Mannose dehydrognenase (GMD) inhibitors 

GMD is critical to the biosynthesis of alginate, the dominant exopolyosaccharide produced in mucoid Pseudomonas aeruginosa strains. Alginate is thus a significant component of the resultant bacterial biofilms and causative towards the growing ineffectiveness of current antibiotic treatments. The biochemical reaction catalysed by GMD is illustrated on the right.

Using a chemoenzymatic strategy, firstly involving chemical glycosyl 1-phosphate synthesis and followed by enzymatic pyrophosphorylation, we have constructed a series of modified sugar nucleotides to probe GMD.

• From our first series of C6-modified structure function tools, a C6-Me homologue of 1 was capable of reversibly preventing production of 2 (Org. Lett., 2019).
• Recently we identified a C6-amide derivative of 2 as a micromolar inhibitor  (ACS Chem. Biol., 2020).
• These discoveries provide a framework for wider inhibition strategies to be developed.