发展高质量的多肽分子探针研究细胞内蛋白质分子功能

项目名称： 发展高质量的多肽分子探针研究细胞内蛋白质分子功能

项目编号： No.21475109

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 数理科学和化学

项目作者： 吴川六

作者单位： 厦门大学

项目金额： 81万元

中文摘要： 针对特定蛋白质分子，发展高质量的多肽分子探针，对于研究该蛋白质分子的功能以及发展新型药物分子等方面的研究都具有重要意义。然而，多肽分子探针设计所面临的一个重大基础化学问题是：如何发展稳定多肽二级或三级结构的方法学，从而设计合成具有固定构象且刚性较强的多肽分子模板，应用于高质量多肽分子探针的构建。本项目拟发展新型多肽结构稳定化方法学，探索决定多肽α-螺旋结构稳定性的关键性因素，设计合成具有独特螺旋结构的多肽分子模板。进一步针对细胞内与疾病密切相关的蛋白质分子，即癌蛋白MDM2和MDMX，发展高亲和力、高特异性和高稳定性的多肽分子探针。深入研究多肽分子探针的序列、结构与其生物活性之间的关系，优化多肽分子探针的化学和生物性能，研究多肽分子探针在复杂生命体系中与靶标癌蛋白的靶向结合能力。进一步以分子探针为工具，研究靶标癌蛋白在细胞内的功能，同时探索多肽分子探针作为靶向抗肿瘤药物分子的潜能。

中文关键词： 分子探针；多肽；蛋白质相互作用；螺旋结构；癌细胞

英文摘要： Developing high-quality peptide probes for targeting specific proteins is of great importance not only for exploring the biological functions of target proteins, but also for the development of novel drug molecules. However, one crucial fundamental challenge in chemistry facing the design of peptide probes remains on how to develop efficient methodology for stabilizing the secondary or tertiary structure of peptides, so as to design and synthesize peptide templates with fixed and rigid conformation, so that being promising for the construction of peptide probes of high quality. In this project, we will develop a novel strategy for the stabilization of peptide conformation, in particular to explore key factors that may contributed to the stability of α-helical structure, so as to obtain peptide templates with unique helical conformation. We will further develop novel peptide probes with high affinity, high specificity and excellent stability that can efficiently target intracellular proteins relevant to human diseases (e.g., the oncoprotein MDM2 and MDMX). In addition, optimizing the quality (or performance) of peptide probes by systematically exploring the associations between peptide sequence, structure and its biological activity, and investigating the target binding capability of peptide probes in complex biological environments. Finally, we will explore the biological roles of the target oncoproteins in cancer cells by using the developed high-quality peptide probes as analytical tools. Moreover, the potential of our peptide probes for targeted anti-cancer therapies will also be examined.

英文关键词： molecular probe;peptide;protein interaction;helical structure;cancer cell