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 a diverse range of molecular structures, themed under a common feature of carbohydrates. This is undertaken to create new tools for chemical biology and for the exploration of non-native carbohydrate-containing motifs in medicinal chemistry.

We are also interested in the growing requirement of such molecules in bioprocesses, especially towards understanding polysaccharide structure-to-function relationships and exploring novel nucleic acid motifs.

We are thus broadly interested in developing new organic and biological chemistry towards the following:

Nucleosides and Nucleotides

Oligosaccharides

Bioprocesses

Nucleosides and Nucleotides

ribose-modified nucleosides

Nucleoside analogues are historically accomplished as medicinal agents for the treatment viruses and cancer.

Here we are developing syntheses of next generation nucleoside analogue structures for evaluation against viral and oncogenic targets.

 

Miller Research Group - Research - Nucleoside Analogues Synthesis

Modifications to Nucleoside Analogues

Nucleic acid building blocks

We are also exploring the synthesis of new building blocks for the enzymatic and chemical assembly of nucleic acids.

 

  • This includes a wide range of ribose-ring modified nucleotide mono- and triphosphates and triphosphorothioates 
Miller Research Group - Research - Nucleoside Analogues Synthesis

Example 4′-thianucleotide triphosphate and a P(III)-amidite.

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 dehydrogenase (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 provided a framework for wider small molecule inhibition strategies to be developed (RSC Chem. Biol. 2023).

 

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

Sugar nucleotide probes and inhibitors of GMD

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.

 

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 (J. Org. Chem. 2023).
  • Heparan and chondroitin sulfate oligosaccharide synthesis, including the use of automated glycan assembly (Org. Biomol. Chem. 2024).
  • Novel methodologies to enable oligosaccharide conjugations.
Miller Research Group - Research - The ubiquitous glycosaminoglycan heparan sulphate

Automated Glycan Assembly of Heparan Sulfates

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

Alginate oligosaccharides

Glycosyl 1-phosphates

Glycosyl 1-phosphates are key intermediates in carbohydrate primary metabolism and have been used as substrates for glycoside phosphorylases (a rapidly expanding family of CAZy enzymes) for the synthesis of oligosaccharide targets.

We recently developed a chemoenzymatic strategy that affords a series of novel unnatural Man-β-1,4-GlcNAc analogues using the β-1,4-mannosyl-N-acetyl-glucosamine phosphorylase, BT1033 (Chem. Sci. 2023).

Miller Research Group - Research - Library of pyranose-modified mannose 1-phosphates

Access to non-native disaccharides using a phosphorylase

Bioprocesses

Coming soon.

Miller Research Group - Research - The ubiquitous glycosaminoglycan heparan sulphate

Funding and Collaborators

FUNDING

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

  • UK Research and Innovation (UKRI) – EPSRC, MRC and BBSRC.
  • Industry – Astra Zeneca, Riboscience LLC, Unilever, Croda, Iceni Glycoscience and Syngenta.
  • The Royal Society of Chemistry.