Expediting glycosaminoglycan synthesis: expanding frontiers for carbohydrate chemical biology

This UKRI Fellowship will support my development of a new scientific expertise at Keele University which interfaces chemistry and biology. The overarching goal of the research is to develop an efficient technology to provide biologically important carbohydrates. Specifically, a class of oligosaccharides (where multiple carbohydrate monomers are linked together to form a chain) called heparan sulfates. Heparan sulfates are very important regulators within biology, mediating pathological conditions including cancer, Alzheimer's disease, viral infections such as HIV and HSV and numerous bacterial infections. Therefore, there is a real need to interrogate and fundamentally understand the biological role that heparan sulfate plays in these processes. This will allow scientists to formulate a precise picture of heparan sulfate-mediated structure-activity relationships and initiate the development of new treatments for the pathophysiologies that they control.

Chemical synthesis of heparan sulfates is particularly challenging and has traditionally always been completed using solution-phase reactions. Whilst there have been significant achievements in this field, the time and resource required to enable such 'total' syntheses is vast and more efficient methods must be found. This challenge will be addressed by automating heparan sulfate production using a machine-based synthesis and then modifying the materials obtained with enzymes to install specific features that enable their biological function. Such a methodology would revolutionise how quickly we can access these materials, which is absolutely necessary to study and understand their ubiquitous regulatory biology.

In undertaking this research, I will adopt a multidisciplinary approach consisting of a fusion between traditional organic chemistry, the evolving field of synthesis automation, and the innovative field of chemoenzymatic modification. This combination will facilitate the development of a faster and greener approach to biologically relevant heparan sulfates and overcome the current challenges presented in the building of biologically important carbohydrates. This is a rapidly evolving worldwide field which is currently underrepresented in UK science. The important materials provided by the technology and knowledge developed during this Fellowship will be used to probe these mechanisms of disease and aid the design and development of new therapeutics against them.

Personal Impact:
This Fellowship embodies the flexibility and opportunity needed to for me establish competence in new scientific methodologies (biochemistry and automation methods) which underpins my establishing a world-leading capability for the expedited provision of structurally defined carbohydrates; this will deliver a huge personal impact for my scientific career.
The impact of this research could also be measured upon new, budding scientists. The School of Chemical and Physical Sciences at Keele is nationally renowned for its inspirational teaching (TEF Gold award), exemplified by a commitment to include cutting edge, research driven scientific content in undergraduate teaching. In a continuation of this philosophy, the staff and student cohort at Keele will benefit from the Fellowship as the research results arising will be incorporated into lectures, and also shared with undergraduate research students completing final year MChem research projects in my group.

Societal Impact
There are just under a thousand cancer diagnoses every day in the UK. Scientific research that can provide materials to explore the pathophysiology of the disease and offer new insight into targets for treatment will be of profound benefit to society. This Fellowship will provide a streamlined methodology for accessing structurally defined carbohydrate materials, essential to study the chemical biology of an enzyme upregulated in tumour metastasis and attributed to a worsened clinical prognosis. In addition, the class of materials targeted in this Fellowship, the glycosaminoglycans, are hugely involved in regulating a number of other disease states that have a deleterious effect on society e.g. Alzheimer's disease and bacterial infection. New chemical tools to better understand these processes will also be assessable more quickly using this Fellowship technology. High quality research published from this Fellowship will therefore create significant public interest in the area because it has a direct impact on quality of people's lives and health. We will strive to engender public enthusiasm by using print and digital media and exhibitions to communicate the role chemistry and biological chemistry play in targeting new medicine development, just as it has continued to do over the last century. Highly publicised and cited work will serve to raise the UK global profile of the disciplines combined in this Fellowship, facilitating new international collaborations, but also encouraging new generations of UK organic chemists to consider more interdisciplinary research career paths.

Economic Impact
The research proposed in this application has great potential impact on the UK pharmaceutical and biomaterial companies working in the areas of chemotherapy treatment and biomaterial applications respectively. The need for faster and greener methods to access biologically relevant and non-native carbohydrate systems will bring forward the opportunity to engage with these exciting biomolecules.