Breaking Down and Building Up: Chemical Tools for the Glycosciences

聚糖是地球上最丰富的有机分子，覆盖在每个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位长的延伸多糖。尽管有证据表明聚糖在生物学中起着至关重要的作用，但我们仍然缺乏对不同聚糖结构与其生物学功能之间联系的分子机制的详细了解。造成这种情况的一个主要原因是缺乏在活细胞环境中操纵聚糖的可用工具。与蛋白质和核酸不同，聚糖的生物合成不是一个模板导向的过程，这限制了对研究这些结构有用的技术工具箱。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糖的生物合成、呈现和最终功能的基本生物学机制。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“构建”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，使我们能够抑制具有挑战性的探针聚糖（o连接结构）的呈现，发明一种优越的合成途径，以获得组装各种聚糖结构所需的代谢前体（核苷二磷酸糖），并在活细胞上设计完全合成的糖萼，从而对表面显示的聚糖提供绝对的分子控制。该研究项目将为高素质人才（HQP）提供宝贵的跨学科研究经验，因为他们不仅可以合成复杂的化学物质，还可以在生物分析中验证该物质。我们的具体目标包括：目标1：开发下一代抑制o -链聚糖生物合成的试剂；目标2：改善合成核苷酸二磷酸糖的途径。目标3：通过胞内糖共聚物合成扩展糖萼工程技术。结合起来，这些目标将填补糖科学中多个未满足的需求，并使未来的研究活动能够深入探索基本的生物过程。

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.