ORGANIC CHEMISTS FOCUSED ON CARBOHYDRATE SYNTHESIS

OUR RESEARCH

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Research Program

The group’s research involves the chemical and chemoenzymatic synthesis of carbohydrates. This is undertaken to create new chemical tools to explore glycobiological function and for the application of non-native carbohydrate structures in medicinal chemistry. We are also interested in the growing requirement of carbohydrates as biomaterials, especially towards understanding polysaccharide structure-to-function relationships.

We are broadly interested in developing new carbohydrate syntheses towards the following:

Oligosaccharides

Nucleoside analogues

Sugar Nucleotides

Oligosaccharides

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.
Miller Research Group - Research - The ubiquitous glycosaminoglycan heparan sulphate

The ubiquitous glycosaminoglycan, heparan sulphate

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.
Miller Research Group - Research - Introducing bioisosteric replacement of carboxylate groups with hydroxamate-modified alginate building blocks

Alginate oligosaccharides

Nucleoside Analogues

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).
Miller Research Group - Research - Nucleoside Analogues Synthesis

Modifications to Nucleoside Analogues

Sugar Nucleotides

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.

 

Miller Research Group - Research - Sugar Nucleotides

GMD catalyses the irreversible formation of the alginate building block, GDP-ManA (2) from GDP-Man (1).

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.

 

Miller Research Group - Sugar Nucleotides - First Micromolar Sugar Nucleotide Inhibitor of GMD

Sugar nucleotide probes and inhibitors of GMD

Funding and Collaborators

FUNDING

We are extremely grateful to Keele University for their continued support of our research, alongside the following Research Councils, industrial partners and charities.

 

COLLABORATORS