基于二肽的手性响应性聚合物：设计及其在手性分离中的应用

Chiral chromatography columns are widely used in analysis and separation of chiral intermediates and drugs. They also play critical roles in modern medicine industry and chirality-related applications. In this research, developing highly efficient chiral chromatographic stationary phase is the key step and attracts scientists' interests significantly. However, in the domestic market, most of products are provided by foreign companies; in contrast, products with independent intellectual properties are quite rare. On the other hand, these commercial products also have many shortcomings and inevitably encounter many problems, such as unsatisfied selectivity and versatility, low separation and loading efficiency, as well as high synthesis costs. Thus, developing new generation of chiral chromatographic separation materials, is quite urgent for the increasingly demand of market. In this project, chirality-responsive polymers based on dipeptides functional units are introduced to the design of chiral chromatographic stationary phase. These polymers exhibit favorable responsibility toward specific chiral molecules; chiral interaction signals could be transferred to macroscopic properties of materials (such as wettability, morphology, rigidity) and bring extra advantages to separation processes. In addition, to improve the separation performance in microfluid channels, various macro- and nano-composite microspheres will be used as inorganic carriers for polymers to construct novel responsive nano-chiral separation materials. Compared with traditional materials, the developing materials can be applied to a wide range of chiral species with high loading efficiency. Meanwhile, dynamic separation process can be modulated intelligently due to the smart features of polymers, which will bring obvious merits for further design. We believe this technology will have wide application perspective, and help develop novel chiral separation products with independent intellectual properties.

手性色谱柱被广泛应用于手性中间体、手性药物等的分离与分析中，在现代制药和手性相关应用中占据着极其重要的地位。其研究的核心是高性能手性色谱固定相的开发。然而，现有手性色谱柱产品都是由国外公司开发的，在我国市场上尚无具有我国独立知识产权的产品出现。而且即使是这些产品，由于受材料的限制，在选择性、通用性、分离效率、柱效、上样量和成本等方面存在诸多问题。因此亟需开发新型的手性色谱分离材料，以满足日益增长的市场需求。本课题创新地将基于二肽的手性响应性聚合物引入到色谱固定相的研发中，并与纳米技术结合，期望开发出新型响应性纳米手性色谱固定相。相比于传统的色谱固定相，研制的材料适用于多种不同类型的手性分子，载药量大，可通过环境条件的改变对分离过程进行智能控制，因而可扩展性强，可以开发为具有我国独立知识产权的手性色谱分离技术和产品，应用前景十分广阔。

本项目的核心思路是开发手性分子响应性聚合物材料，并将其应用到手性物质的分离和纯化领域。申请人系统总结了基于手性识别–氢键介导–功能主链的手性分子响应性智能聚合物的设计思想，创新性地提出可以在材料与手性分子相互作用的过程中，借助表面浸润性、硬度、粘弹性等性质的大幅转变，扩大手性分子间的差异性，实现手性对映体的色谱分离。开发出的基于二肽修饰的聚乙烯基亚胺材料，可以通过手性单糖调控表面浸润性的大幅转变，首次实现了对单糖对映体的色谱分离，同时还展现出对不同种类的单糖、二糖及寡聚多糖的显著分离，达到了目前色谱领域对糖类物质分离的最高水平。随后，我们将研究的重心放在新型磷酸化肽、糖肽富集材料的开发上。申请人创新地提出通过多重弱氢键相互作用，实现对多磷酸化肽的选择性结合。聚合物薄膜对多磷酸化肽具有很强的特异性吸附能力，同时能够通过溶剂极性、pH、温度等参数，对多磷酸化肽在材料表面的吸附行为进行动态的调控，打破了主流无机氧化物材料对该领域的垄断。开发出了基于二肽的聚合物材料平台，其展现出对糖肽超高的富集选择性，能够从1000倍BSA的干扰中，准确地捕获到目标糖肽；同时材料还展现出对不同种类的单糖、寡聚多糖、不同连接方式的糖链精确的区分能力。我们的材料首次将糖肽的高选择性富集和糖链精确区分融为一体，代表着新一代糖肽富集材料的特征。进一步我们开发的基于PAM-g-Allose的聚合物材料，打破了疏水材料无法用于糖肽富集的认识限制，实现了对唾液酸糖肽的高选择性富集。在这些研究基础上，申请人系统总结了聚合物基富集材料的研究现状，分析了智能聚合物材料在蛋白质组学中应用的可行性和优越性，申请人预测翻译后修饰蛋白质组学将成为智能聚合物材料一个新的应用方向，.在国家基金委有机高分子材料学科面上项目基金的资助下，申请人开展了一些创新性的研究工作，在《Nature Communications》、《Angew. Chem. Int. Ed.》、《J. Am. Chem. Soc.》、《Adv. Mater.》、《NPG Asia Materials》杂志上发表了六篇研究论文，另有多篇研究论文分别发表在《ACS Applied Materials & Interfaces》（4篇），《J. Mater. Chem. B》（1篇）和《Scientific Report》（2篇）等杂志。