EPSRC-SFI: Glycoconjugate tools for sensing endoglycosidase activity: a diagnostic sugar probe for heparanase

This work will use exploratory scientific research to help further understand, and potentially disrupt, the way that cancer cells spread. This process is called angiogenesis and is central to all cancers. A critical part of angiogenesis is controlled by enzymes within cells that regulate the extracellular environment. More specifically, these enzymes act by breaking down biologically important carbohydrate molecules, called heparan sulfates, whose function is to switch on cellular signalling cascades, effectively initiating angiogenesis. We intend to design and synthesise a series of molecular carbohydrate tools that would be capable of detecting the activity of one of these key enzymes, called heparanase. Using our combined inter-disciplinary knowledge of synthetic carbohydrate chemistry and molecular sensing technology we will design and build molecular probes that can detect the activity of heparanase. The existence of this technology would then enable the future development of research programmes that use these tools to screen for and subsequently select potential inhibitors of heparanase, providing a route towards new therapeutic strategies against cancer.

This Partnership Programme will have strategic impacts for RoI and for UK. For RoI, it is in-line with the National Research Prioritisation Strategy 2018-2023 (Health and Wellbeing; Diagnostics and Therapeutics). It will foster and ensure Irish reputation for excellence in research and education, training and in the career development of young researchers. From a UK perspective, the research is coherent with the prioritised research disciplines highlighted by EPSRC and typified by supporting research in Chemical Biology and Biological Chemistry as a growth area. In addition, the Association of the British Pharmaceutical Industry highlights in their January 2019 report the changing landscape of this sector and the skills required for the UK to maintain its leading position as a hub for medicines and vaccines research and development. The ability to synthesise complex organic molecules will contribute directly to this skill requirement. Our proposal will be a platform for forming strategic links with industry, and it will support our Outreach Programme. Our key focus is to continue to strengthen established collaborations and achieve a sustainable platform for future UK-RoI activity through leveraging Irish, European, international or industrial funding for ongoing joint research projects. Our proposed work has been designed to deliver on high impact research, where the development of novel FRET probes for heparanase and their application in probing enzymatic activity is the central research theme. This is highly topical and competitive area of research. However, as our proposal demonstrates, our ideas are both innovative and challenging, where in a strategic manner organic structures and molecular probes possessing rich photophysical properties are designed and employed through the use of enzymatic activation and high-throughput assays. We have identified feasible deliverables. We strongly believe that the consortium consisting of both the Keele and TCD teams and project partners (from the UK) have the knowledge, experience and infrastructure to deliver on these successfully. We foresee that in the long run, the outcome of our investigations will directly benefit UK and Irish society and economy with the generation of high-value added material, increase in intellectual property, and through the generation of highly skilled researchers and workforce. Given the nature of the proposed research, the impact and the experience acquired from this programme will have benefits beyond the RoI and UK as initial dissemination of the results will be in the form of publications in high impact journals and presentations at national and international meetings. We predict that the results from this work will have a significant influence on the future developments of sensing, diagnostic and imaging research, where also at the same time as providing the researcher with valuable new experience in multidisciplinary fields. We have in place a management plan to enable real transfer of knowledge between highly skilled and well-trained researchers to take place between these two institutes, this being a major delivery target: 'to stimulate new collaborations and exchange existing collaborations of strategic relevance between excellent researchers and research institutes. This will have major educational impact, which will result in establishing long-term arrangements for student exchange and access to equipment and training.