Chemical biology strategies for discovery and profiling of glycan-protein interactions.

在所有生命体中，细胞表面都覆盖着糖。不同的糖单位组合成复杂的分支结构，称为聚糖。这些聚糖长期以来被认为只是提供了一个物理屏障，一个糖层来保护细胞的完整性。我们现在已经认识到，这些复杂的分子含有对细胞正常运作非常重要的生化信息。有趣的是，这些信息可以被称为凝集素（蛋白质）的其他分子读取，凝集素可以与聚糖结合，并在生命中发挥重要的生物学作用。例如，这些结合事件涉及细胞与其他组织的粘附，但也涉及细胞之间的通讯。最近，人们发现癌细胞利用聚糖和凝集素的方式有助于疾病的进展。这些发现引发了对靶向聚糖和凝集素治疗方法的研究，但聚糖和凝集素的研究仍然非常困难。在许多情况下，人们对聚糖-凝集素的识别知之甚少。这在很大程度上是由于它们的复杂性和缺乏合适的化学和生化工具来剖析这些相互作用。在本研究计划中，我建议在化学和生物学的界面上开发策略来发现，表征和调节这些聚糖-凝集素结合事件。我们将使用包括化学合成、凝集素生化操作和活细胞实验在内的技术组合，以产生工具和概念，这将促进我们对这些分子作用的理解。这些工具将包括新的探针，可以捕获相互作用的分子，并通过分析技术进行后续鉴定。

Across all kingdoms of life, the surface of cells is covered with sugars. Various sugar units are assembled into complex branched structures called glycans. These glycans were long thought to only provide a physical barrier, a sugar layer to protect the integrity of the cell. We have now realized that these complex molecules contain biochemical information that is highly important for the proper functioning of the cell. Interestingly, this information can be read by other molecules called lectins (proteins) that can bind to glycans and mediate important biological roles for life. For example, these binding events are involved in the adhesion of cells to other tissues but also in the communication between cells. Recently, it was discovered that cancer cells exploit glycans and lectins in a way that is contributing to the progression of the disease. These discoveries have triggered research into targeting glycans and lectins in therapeutic approaches but the study of glycans and lectins remains extremely difficult. In many cases, glycan-lectin recognition is poorly understood. This is in large part due to their complexity and the lack of suitable chemical and biochemical tools to dissect these interactions. In this research program, I propose to develop strategies at the interface of chemistry and biology to discover, characterize and modulate these glycan-lectin binding events. We will use a combination of techniques including chemical synthesis, biochemical manipulation of lectins, and live cell experiments in order to generate tools and concepts that will advance our understanding of the roles of these molecules. These tools will comprise novel probes that allow the capture of the interacting molecules and subsequent identification through analytical techniques.