活性O-聚糖的化学合成及其靶向性机制研究

Glycosylation is one of the most important post-translational modifications of the protein, which is related to many activities of life. There are two major glycosylation types, N-linked and O-linked. The sugar chains of glycoproteins play an important role in the growth, invasion and metastasis of tumor cells. Unlike N-linked glycans, targeting and functional mechanisms of O-linked glycans in tumors is not clear yet. Since extraction and isolation of O-glycans from cells or tumor tissues is tedious and enzymatic preparation of them is also problematic, chemical synthesis of glycans is the most popular approach at current stage. The aim of this project is to develop a concise method for the synthesis of a series of O-linked glycans, from Core 1 to Core 8. Also, we will use the synthetic O-glycans as probe in combination with chip technology, to study glycan-protein interactions and screen potential new target molecules of O-glycans. In addition, the structural modifications, structure-activity relationship and molecular mechanisms of biologically active O-linked glycans will be also understood. The project can not only help to clarify the targeting mechanisms of biologically active O-linked glycans, but also provide solid theory foundation for anti-cancer drug discovery.

蛋白质糖基化是一种重要的翻译后修饰，它参与和调控生物体的许多生命活动。N-连接和O-连接聚糖是生物体内蛋白质糖基化的两大修饰类型，相关糖链在肿瘤生长、侵袭与转移中发挥重要作用。相较于N-聚糖的研究，O-聚糖在肿瘤中靶向性及其功能机制研究还不甚清楚。鉴于通过提取分离手段从细胞或肿瘤组织中得到所需的O-聚糖很困难，酶法合成聚糖亦存在着诸多问题，目前化学方法合成糖链是最佳的选择。因此本课题拟发展O-聚糖化学合成策略，合成O-聚糖核心结构Core 1 - Core 8；并以合成的O-聚糖为探针，结合芯片技术，进行O-聚糖与功能性蛋白质相互作用研究，发现O-聚糖潜在靶分子；同时，对潜在靶向O-聚糖进行结构修饰、构效关系及其分子机制研究。研究项目不但可以帮助阐明活性O-聚糖的靶向性机制，而且为聚糖类抗肿瘤药物的发现研究提供坚实理论基础。

O-聚糖参与很多细胞生化过程，诸如细胞粘附、细胞免疫、血液凝固等，但由于聚糖结构的多样性与微观不均一性，其广泛的分子靶向性、其与功能性蛋白质相互作用及其功能机制研究仍然鲜见报道。本课题以O-聚糖中core 1的化学全合成研究为基础；选择特定活性的糖基供体离去基团，以及合适的保护基团进行糖基化反应，利用NMR、MS进行结构鉴定；最终，得到了结构确定的core 1 O-聚糖及其衍生物，并合成了一种新型化合物；创建一套新的高效O-糖类化合物的合成策略。本课题的相关研究成果不但可以帮助阐明活性O-聚糖的靶向性机制，而且为高水平聚糖类创新性药物的发现研究提供坚实理论基础。