Chemical Biology Tools for Probing and Discovering Glycan-Protein Interactions

所有生命系统的细胞都被一层“糖衣”包裹着，糖衣由碳水化合物与蛋白质(称为糖蛋白)或脂类(称为糖脂)共价连接而成。细胞表面发现的碳水化合物，也被称为多糖，通过调节一系列重要的生物学过程对正常生理至关重要，也直接与每一种重大疾病有关。通过与糖链结合蛋白的高度选择性相互作用，细胞表面的糖链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得到了很好的认识，但我们目前对这些关键结合事件中涉及的多糖结构的了解是有限的。事实上，碳水化合物和糖科学领域的研究远远落后于生命的其他生物分子(蛋白质、脂类、核酸)。造成这种认识差距的一个主要原因是有效地合成和研究具有生物相关性的复杂多聚糖结构的化学工具有限。我们的跨学科研究计划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了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、与生物相关的复杂糖链结构，这些结构是研究这些分子如何与蛋白质相互作用所必需的。我们还将开发新的化学工具来探索糖与蛋白质的相互作用，特别是在基于细胞的平台上，因为目前缺乏关于复杂多糖的细胞功能的信息。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，并将使人们能够更好地理解复杂的多糖如何与蛋白质相互作用并引发细胞中的功能。从这个研究项目中获得的知识将使我们能够回答快速发展的糖科学领域中化学和生物学交界处的基本问题。在该计划中培训的HQP将处于开发新化学技术的前沿，这些技术将使该领域进入新的方向，他们将获得各种跨学科技能，包括有机合成、生物化学、分子生物学、酶学和化学生物学方面的专业知识。

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.