Application of activity-based glycosidase probes for mechanism, enzyme discovery and clinical diagnosis

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An expanding human civilization is under enormous pressure to find environmentally sustainable approaches to providing food, energy, diagnostics and medicines. By 2030, approximately 50% more food will need to be produced from the same area of land, but with less water, more expensive energy, and with the constraints and impact of climate change. The demand to replace environmentally damaging fossil fuels by renewable energy and sustainable feed stocks is equally urgent. An expanding and ageing global population faces accelerating health problems such as infectious and inherited disease, antimicrobial resistance and dementia, placing an enormous burden on health and social services, unless new therapeutic approaches are developed. The development of new approaches to dissect the diverse and wonderful roles for carbohydrates in living cells is now a major challenge for modern cell biology, biochemistry and medicine. The colossal potential of carbohydrates is reflected in the multiplicity of functions for glycans; in addition to acting as energy sources, carbohydrates play central roles in cell and organism structure, communication (carbohydrates are "the language of the cell"). Indeed, we stand on the cusp of an exciting new "glyco-age" which expands beyond the understanding of cellular roles for glycans, through to the development of new carbohydrate-based vaccines and drugs and diagnostics. What scientists and society need, are tools that allow us to probe and utilize carbohydrate chemistry. This grant submission aims to develop and apply a new class of chemical reporter we have developed. These "activity-based probes" will allow us to make breakthroughs in different areas of carbohydrate science; linked by a common method. We will1. Develop and apply chemical tools for enzyme discovery - allowing us to identify the enzymes industry needs for sustainable energy production2. Expand these tools into areas of human health and disease: building upon fundamental academic insight to deliver diagnostics for inherited disease and cancerResearch in these two areas will be highly synergistic with medical tools aiding biotechnology and vice versa. Carbohydrates have for a long time been a challenging area of "Cinderella science". New tools, new approaches and new ways of working will help society benefit from the power and promise of carbohydrates.