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

在所有生命王国中，细胞表面都覆盖着糖类。不同的糖单元被组装成复杂的分枝结构，称为多糖。长期以来，这些多糖被认为只是提供了一种物理屏障，一种保护细胞完整性的糖层。我们现在已经意识到，这些复杂的分子包含对细胞正常运作非常重要的生化信息。有趣的是，这种信息可以被其他被称为凝集素(蛋白质)的分子读取，这些凝集素可以结合到多糖上，并在生命中扮演重要的生物角色。例如，这些结合事件不仅参与细胞与其他组织的黏附，而且还参与细胞之间的交流。最近，人们发现癌细胞利用多糖和凝集素的方式促进了疾病的发展。这些发现引发了针对多糖和凝集素的治疗方法的研究，但对多糖和凝集素的研究仍然非常困难。在许多情况下，人们对糖凝集素的识别知之甚少。这在很大程度上是因为它们的复杂性，以及缺乏适当的化学和生化工具来剖析这些相互作用。在这个研究计划中，我建议在化学和生物学的界面上制定策略，以发现、表征和调节这些糖-凝集素结合事件。我们将使用包括化学合成、凝集素的生化操作和活细胞实验在内的技术组合，以产生将促进我们对这些分子的作用的理解的工具和概念。这些工具将包括新的探针，允许捕获相互作用的分子，并随后通过分析技术进行识别。

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.