均一结构糖蛋白γ干扰素的化学合成研究

Scientific research on proteins has been a hot area in the discipline of life science, as it is an essential mean for people to explore and understand life. The preparation of proteins utilizing chemical methods has become a frontier of chemical biology. In particular, chemical synthesis of homogeneous glycoproteins affords us a key to study the relationship between their structure and function, as well as to explore the related field. In this proposal, we will focus on the development of novel synthetic methods and their applications to the synthesis of protein interferon-γ in a homogeneous glycoform. On the basis of this study, we would be able to further study the specific topics, such as how specific carbohydrate structures affect the properties and functions of glycoproteins, which are inaccessible via traditional biochemical methods. We believe this research will be of significant benefit to scientific community for understanding the roles of protein glycosylation, as well as the structure function relationship of large biological molecules. It will also provide us useful knowledge for developing protein-based and -related therapeutics, and have a huge impact on the allied areas of life science.

以蛋白质为对象的研究是生命科学的热点领域，是人类探索生命奥秘的重要途径。应用化学方法进行蛋白质，特别是含均一结构糖基取代蛋白质的全合成，是研究糖蛋白结构功能、探索相关领域的一个重要手段，是当今化学生物学领域的一个前沿方向。本项目中我们将针对糖蛋白进行化学合成研究，从发展新颖高效的合成方法学以及重要糖蛋白分子γ-干扰素的全合成两方面入手，通过方法创新，高效地得到结构确定、产物均一的蛋白质及其相应的糖基取代形式。在此基础上，我们将能够针对目前依靠生物技术难以涉及的领域，如特定糖基取代对蛋白质性质及功能的影响等进行深入地探索和研究。该项目的研究，将有助于扩展和加深人们对蛋白糖基化作用的理解，拓展人们对生物大分子结构及其作用机理的认识，为以糖蛋白为基础以及相关的药物开发提供极为有用的信息，也将会对生命科学相关领域的发展产生意义深远的影响。

本项目在《资助项目计划书》基础上开展工作，在执行期内基本完成预期目标，四年内针对多肽片段在赖氨酸位点连接的选择性问题，开展了以下几方面工作：1）发展了基于β-巯基赖氨酸衍生物、赖氨酸位点无需保护的α-选择性多肽片断连接方法；2）运用赖氨酸连接方法学完成了γ-干扰素的全合成，并探索了其非天然氨基酸改造和糖基化修饰形式的合成；3）化学合成了趋化因子CXCL14及其定点甲硫氨酸氧化修饰物，并评估了相应的细胞趋化活性。这些工作为多肽片段在赖氨酸位点的连接提供了高效可行的方案，也为通过化学合成手段研究蛋白质翻译后修饰积累了经验。项目执行期内，研究团队在Org. Lett.、J. Org. Chem.等期刊上发表SCI论文2篇；项目负责人获得国家自然科学基金优秀青年基金、重大研究计划（培育）等项目资助。