Chemical Biology Tools for Probing and Discovering Glycan-Protein Interactions

所有生命系统的细胞都被一层由碳水化合物组成的“糖涂层”包围着，这些碳水化合物与蛋白质（称为糖蛋白）或脂质（称为糖脂）共价相连。在细胞表面发现的碳水化合物，也被称为聚糖，通过介导一系列重要的生物过程，对正常生理至关重要，也直接参与每一种重大疾病。通过与聚糖结合蛋白的高度选择性相互作用，细胞表面聚糖启动或调节细胞中的特定功能。虽然这些相互作用的重要性是公认的，但我们目前对这些关键结合事件中涉及的聚糖结构的理解是有限的。事实上，碳水化合物和糖科学领域的研究明显落后于其他生命生物分子（蛋白质、脂质、核酸）。造成这种知识差距的一个主要原因是化学工具的可用性有限，无法有效地合成和研究生物相关的复杂聚糖结构。我们的跨学科研究项目将通过开发创新的化学生物学工具和策略来解决这些问题，这些工具和策略将用于研究和理解碳水化合物与蛋白质相互作用的机制。这将通过两个主要目标来实现。我们将开发有效的化学-酶策略，使人们能够获得知之甚少的、生物相关的复杂聚糖结构，这些结构需要能够研究这些分子如何与蛋白质相互作用。我们还将开发新的化学工具来探测聚糖-蛋白质的相互作用，特别是在基于细胞的平台上，因为目前缺乏关于复杂聚糖细胞功能的信息。由此产生的新的化学工具箱将使糖科学领域的广泛研究人员受益，并将使人们更好地了解复杂的聚糖如何与蛋白质相互作用并在细胞中引发功能。从这个研究项目中获得的知识将使我们能够在快速发展的糖科学领域回答化学和生物学界面的基本问题。在这个项目中接受培训的HQP将站在开发新的化学技术的最前沿，这些技术将使该领域进入新的方向，他们将获得有机合成、生物化学、分子生物学、酶学和化学生物学等多种跨学科技能。

Cells of all living systems are surrounded by a “sugar coating” that is composed of carbohydrates covalently linked to proteins (called glycoproteins) or lipids (called glycolipids). The carbohydrates found on cell-surfaces, also called glycans, are crucial for normal physiology by mediating a range of important biological processes, and are also directly involved in every major disease. Through highly selective interactions with glycan-binding proteins, cell-surface glycans initiate or modulate specific functions in cells. While the importance of these interactions is well recognized, our current understanding of the glycan structures involved in these crucial binding events is limited. Indeed, research in carbohydrates and the glycosciences field significantly lags behind other biomolecules of life (proteins, lipids, nucleic acids). A major reason for this knowledge gap is that there is a limited availability of chemical tools to efficiently synthesize and study biologically relevant complex glycan structures. Our interdisciplinary research program will address these issues by developing innovative chemical biology tools and strategies that will be used to study and understand the mechanisms by which carbohydrates interact with proteins. This will be achieved through two main aims. We will develop efficient chemo-enzymatic strategies that will enable access to poorly understood, biologically relevant complex glycan structures that are needed to be able to study how these molecules interact with proteins. We will also develop new chemical tools to probe glycan-protein interactions, particularly in cell-based platforms as information on the cellular function of complex glycans is currently lacking. The resulting new chemical toolbox will benefit a broad range of researchers in the glycoscience field and will enable an improved understanding of how complex glycans interact with proteins and elicit functions in cells. Knowledge gained from this research program will allow us to answer fundamental questions at the interface of chemistry and biology in the rapidly progressing field of glycosciences. HQP trained in this program will be at the forefront of developing new chemical technologies that will progress the field into new directions and they will obtain a diverse interdisciplinary skill set with expertise in organic synthesis, biochemistry, molecular biology, enzymology, and chemical biology.