Breaking Down and Building Up: Chemical Tools for the Glycosciences

分解与构建：糖科学的化学工具

• 批准号: RGPIN-2022-04437
• 负责人: Edgar, Landon
• 金额: $ 1.82万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762115
• 关键词: Breaking; Down; Building; Up; Chemical

Glycans are the most abundant organic molecules on the planet and coat the surface of cells in every known organism. These structures can range in size from simple monosaccharides to extended polysaccharides hundreds of units long. Despite evidence that glycans play critical roles in biology, we still lack a detailed understanding of the molecular mechanisms that link diverse glycan structures to their biological function(s). A major reason for this has been a dearth of available tools to manipulate glycans in the context of live cells. Unlike proteins and nucleic acids, biosynthesis of glycans is not a template-directed process, which limits the toolbox of technologies that are useful for studying these structures. My research program is focused on the design and synthesis of chemical probes and reagents that will enable glycoscientists to better understand the basic biological mechanisms that govern glycan biosynthesis, presentation, and ultimately function. Our approach is to harness synthetic chemistry to create platforms that allow us `break down' and `build up' glycans with a focus on molecular detail. Over the next five-years, we will develop reagents that will allow us to inhibit presentation of challenging-to-probe glycans (O-linked structures), invent a superior synthetic route to access the metabolic precursors (nucelotide diphosphate sugars) required to assemble a broad range of glycan structures, and engineer completely synthetic glycocalyces on living cells that will provide absolute molecular control over surface-displayed glycans. This research program will provide highly-qualified personnel (HQP) with valuable interdisciplinary research experiences as they will not only synthesize sophisticated chemical matter, but also validate this material in biological assays. Our specific aims include: Aim 1: Develop next-generation reagents for inhibiting O-linked glycan biosynthesis Aim 2: Improve access to synthetic nucleotide diphosphate sugars. Aim 3: Expand glycocalyx engineering technologies via on-cell glycopolymer synthesis. Combined, these aims will fill multiple unmet needs in the glycosciences and enable future research activities that deeply probe fundamental biological processes.

聚糖是地球上最丰富的有机分子，覆盖在每种已知生物的细胞表面。这些结构的大小可以从简单的单糖到数百个单元长的多糖。尽管有证据表明聚糖在生物学中起着关键作用，但我们仍然缺乏对将不同聚糖结构与其生物学功能联系起来的分子机制的详细了解。其主要原因是缺乏可用的工具来操纵活细胞中的聚糖。与蛋白质和核酸不同，聚糖的生物合成不是模板导向的过程，这限制了用于研究这些结构的技术工具箱。我的研究项目集中在化学探针和试剂的设计和合成，这将使糖科学家更好地了解控制聚糖生物合成，呈现和最终功能的基本生物机制。我们的方法是利用合成化学来创建平台，使我们能够“分解”和“建立”聚糖，重点关注分子细节。在接下来的五年里，我们将开发试剂，使我们能够抑制挑战探针聚糖（O-连接结构）的呈现，发明一种上级合成路线，以获得组装广泛聚糖结构所需的代谢前体（nucelotide二磷酸糖），并在活细胞上设计完全合成的糖萼，这将对表面展示的聚糖提供绝对的分子控制。该研究计划将为高素质人员（HQP）提供宝贵的跨学科研究经验，因为他们不仅将合成复杂的化学物质，而且还将在生物测定中验证这种材料。我们的具体目标包括：目标1：开发下一代抑制O-连接聚糖生物合成的试剂目标2：改善合成核苷酸二磷酸糖的获得。目的3：通过在细胞上合成糖聚合物拓展糖萼工程技术。结合起来，这些目标将填补糖科学中多种未满足的需求，并使未来的研究活动能够深入探索基本的生物过程。