Miller Group

Research Program

The group's research is focused around the chemical and chemoenzymatic synthesis of carbohydrates. This is undertaken to create new probes for chemical glycobiology 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 from the perspective of accessing materials to understand polysaccharide structure-function relationships.

Broadly, we are interested in developing new carbohydrate syntheses in the following areas:

Sugar nucleotides

GDP-D-Mannose with pyranose structural modifications
erers of cystic fibrosis are at extremely high risk for contracting chronic lung infections. Over their lifetime, one bacterial strain in particular, Pseudomonas aeruginosa, becomes the dominant pathogen. Bacterial strains incur loss-of-function mutations in the mucA gene that lead to a mucoid conversion, resulting in copious secretion of the exopolysaccharide alginate. Strategies that stop the production of alginate in mucoid Pseudomonas aeruginosa infections are therefore of paramount importance. To aid in this, we have created a series of sugar nucleotide tools to probe an enzyme critical to alginate biosynthesis, guanosine diphosphate mannose dehydrogenase (GMD, enzymatic oxidation pathway illustrated below).

Screenshot 2020-05-04 at 14.11.56
GMD catalyzes the irreversible formation of the alginate building block, guanosine diphosphate mannuronic acid (2) from GDP-D-Mannose (1) .

Using a chemoenzymatic strategy, we accessed a series of modified sugar nucleotides and identified a C6-amide derivative of (
2) as a micromolar inhibitor of GMD (ACS Chem. Biol., 2020). This discovery provides a framework for wider inhibition strategies against GMD to be developed.

First micromolar sugar nucleotide inhibitor of GMD

This discovery followed our first series of C6-modified structure function tools for GMD (Org. Lett., 2019; Carbohydr. Res., 2019) and has enabled us to develop small library of modified GDP-D-mannose analogues for wider evaluations (below).

Screenshot 2020-12-17 at 11.42.32
Library of pyranose-modified GDP-mannoses

Glycosyl 1-phosphates

Using synthesis to enable access to non-native mannose 1-phosphates
Glycosyl 1-phosphates are key intermediates in carbohydrate primary metabolism and are utilised by microorganisms to form polyphosphate architectures that constitute keys parts of their extracellular capsule and cell walls. They serve as precursors to sugar-nucleotides, the sugar-donor components utilised by glycosyltransferases in the assembly of oligosaccharides and glycans, and have played a key role in the development of glycosylated natural-product-based therapeutics. Additionally, glycosyl 1-phosphates have been used as substrates for glycoside phosphorylases (a rapidly expanding family of CAZy enzymes) for the synthesis of oligosaccharide targets and also play important technological roles in the food and detergent sectors.

From a synthetic perspective, several options exist to create glycosyl 1-phosphates, most commonly
via anomeric glycosylation or hemi-acetal deprotonation and reaction with a suitable phosphorous electrophile. We have recently utilised such strategies to access a series of non-native mannose 1-phosphates, illustrated below and published here: ACS Chem. Biol., 2020; Org. Lett., 2019; Carbohydr. Res., 2019. We have also developed a modified Madonald phosphorylation procedure, offering rapid access to non-native 1-phosphates directly from acetylated precursors (Carbohydr. Res., 2020, Molbank, 2019).

Screenshot 2020-12-17 at 12.01.32
Library of pyranose-modified mannose 1-phosphates


The synthesis of oligosaccharide targets remains a cornerstone of glycoscience research and we have several projects ongoing in this area that are both fundamental and linked to the industrial importance of carbohydrates. In regard to this latter aspect we have collaborative BBSRC PhD projects running with both Croda and Unilever looking at the utility of carbohydrate based fragments and materials within their respective company product portfolios.

Synthetic approaches to glycosaminoglycans
We are interested in the development of new synthetic methodologies to access the complex and ubiquitous glycosaminoglycan, heparan sulfate.

Screenshot 2019-05-31 at 09.44.16
The ubiquitous glycosaminoglycan heparan sulphate

Following previous work by GJM as a PDRA with Dr J. M. Gardiner at the University of Manchester (See:
Chem. Commun., 2015; Chem. Sci., 2015; Nat. Commun, 2013; Chem. Sci., 2013) we are currently developing new approaches to:

1) Building blocks containing D-GlcN, D-GlcA and L-IdoA . Most recently here we developed an efficient chemical synthesis of a sulfated D-GlcN library and evaluated cell proliferation capabilities of these compounds (
Carbohydr. Res., 2020).

Screenshot 2020-12-17 at 15.36.22

Access to α- and β-O-methyl glycosides of D-GlcN with O6 sulfation and variant N-substitution

2) Methodologies for oligosaccharide assembly

3) Conjugate fluorogenic components to glycosaminoglycans (
RSC Chem. Biol., 2020).

This is being undertaken as part of current EPSRC-SFI and UKRI Future Leaders Fellowship grants and achievements in this area will be posted soon. There is also a broad interest in glycosaminoglycan research at Keele University and we are part of an ongoing collaboration with Mark Skidmore, Scott Guimond, Marcelo Lima, where we recently reported the first involvement of heparin binding to the 2019 (SARS-CoV-2) surface protein (
BioRxiv, 2020). We also recently reported the inhibition of BACE1 (an enzyme implicated in Alzheimer's disease) using a chondroitin sulphate extract (Neur. Regen. Res., 2020)

Synthetic approaches to alginate oligosaccharides
We are also working on the synthesis of modified alginate targets and recently published the first examples of hydroxamate-modified disaccharide alginate building blocks (Org. Biomol. Chem, 2019, 17, 9321–9335; Molbank, 2020, 2020, M1111).

Screenshot 2020-12-17 at 15.39.31

Introducing bioisosteric replacement of carboxylate groups with hydroxamate-modified alginate building blocks

Nucleoside analogues

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 Biotech
Riboscience LLC. For our recent review on the use of nucleoside analogues as anticancer agents, see: Molecules, 2020 and Science 2020.

molecules-25-02050-ag-550 (1)

We are extremely grateful to Keele University, the Research Councils (UKRI, EPSRC, BBSRC & SFI) and industry (Riboscience LLC, Croda & Unilever) for funding our research.

Also, our excellent collaborators:

Prof. Rob Field, Manchester Institute of Biotechnology
Prof. Eoin Scanlan, Trinity College, Dublin
Dr Mark Smith, Stanford University & Riboscience LLC
Dr Martin Fascione, York University
Dr Mark Skidmore, Keele
Dr Scott Guimond, Keele
Dr Marcelo Lima, Keele
Dr Matthew O'Brien, Keele