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

不断扩张的人类文明面临着巨大的压力，需要找到环境可持续的方法来提供食物、能源、诊断和药物。到2030年，同样面积的土地将需要生产大约50%以上的粮食，但用水更少，能源更昂贵，并受到气候变化的限制和影响。用可再生能源和可持续原料取代破坏环境的化石燃料的需求同样紧迫。不断扩大和老龄化的全球人口面临着传染病和遗传性疾病、抗微生物药物耐药性和痴呆症等日益严重的健康问题，除非开发出新的治疗方法，否则将给卫生和社会服务带来巨大负担。开发新的方法来剖析碳水化合物在活细胞中的各种奇妙作用，是现代细胞生物学、生物化学和医学面临的主要挑战。碳水化合物的巨大潜力反映在聚糖功能的多样性上；除了作为能量来源，碳水化合物在细胞和生物体的结构、交流（碳水化合物是“细胞的语言”）中起着核心作用。事实上，我们正站在一个令人兴奋的新“糖时代”的尖端，它超越了对聚糖细胞作用的理解，通过开发新的基于碳水化合物的疫苗、药物和诊断方法。科学家和社会需要的是能让我们探测和利用碳水化合物化学的工具。本次拨款申请旨在开发和应用我们开发的一类新的化学报告。这些“基于活动的探测”将使我们在碳水化合物科学的不同领域取得突破；用共同的方法连接。我们will1。开发和应用酶发现的化学工具-使我们能够确定可持续能源生产所需的酶工业2。将这些工具扩展到人类健康和疾病领域：以基本的学术见解为基础，提供遗传疾病和癌症的诊断。这两个领域的研究将与辅助生物技术的医疗工具高度协同，反之亦然。长期以来，碳水化合物一直是“灰姑娘科学”的一个具有挑战性的领域。新的工具、新的方法和新的工作方式将帮助社会从碳水化合物的力量和前景中受益。

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.