利用动态共价键组装基于α-环肽的单分子人工通道及其功能研究

The study of synthetic transport systems, especially artificial channels, not only can provide insights into the mechanism of natural channels, but also can lead to potential therapeutics, as well as technologies in separation, purification and sensing. Compared to self-assembled channels, unimolecular channels have stable conformations to achieve high efficiency and selectivity, and are receiving more and more attention. However, the unimolecular channels are often structurally complicated. Thus, the preparation of a single tubular molecule that is long enough to span the bilayer has been a challenge in this field. Dynamic covalent chemistry (DCC) combines the robustness of covalent bonds with the error-correction and proof-reading ability of noncovalent self-assembly. In this project, we would like to utilize DCC to develop a novel and efficient protocol to construct unimolecular channels with stable conformations. The artificial channels are designed by introducing side chains into the cyclic α-peptide backbones. The DCC and the intermolecular hydrogen bonding are used to induce the cyclic peptides to self-assemble into unimolecular channels. On the basis of the above study, we will further derive a method to build unimolecular channels in the lipid bilayers in situ via dynamic covalent chemistry. This project will provide a novel strategy for constructing artificial transmembrane transport channels, and will lay a solid foundation for the development of functionalized artificial channels.

对人工跨膜输送体系，特别是人工跨膜通道的研究不仅能为深入理解通道蛋白结构与功能的关系提供简单的模型，同时也为相关疾病的治疗提供新的思路、发展新的分离纯化方法和传感技术。相对于超分子自组装人工通道，单分子人工通道由于具有更高的结构稳定性以及更好的输送效率和选择性而逐渐受到重视。但是，单分子人工通道的结构比较复杂，如何通过共价合成高效构筑长度足以穿透脂双层的管状分子成为该研究领域的难点。本项目拟利用动态共价键既有较高稳定性，又可自我校正、纠错的特点，发展一类新的、可以构筑结构稳定的单分子人工通道的高效方法。拟以α-环肽为骨架，通过引入含有不同官能团的侧链，利用动态共价键和骨架间氢键驱动组装形成结构稳定的单分子人工通道。在此基础上，我们拟进一步研究在脂双层中利用动态共价键原位构筑单分子人工跨膜通道的方法。本项目将建立一种构筑人工跨膜通道的新策略，为发展功能化人工跨膜通道奠定基础。

在细胞中，离子以及氨基酸、水、糖类等具有生物活性的小分子物质进出细胞需要依靠具有跨膜输送能力的通道蛋白的输送。近年来，为了对天然通道蛋白的传输机制进行研究，并对通道蛋白的功能进行模拟，化学工作者以天然通道蛋白为原型，发展了种类繁多的人工跨膜通道体系。人工合成跨膜通道经过多年的发展已经取得了巨大进步，其中单分子人工跨膜通道由于具有更高的结构稳定性、高选择性以及传输效率而受到化学工作者的关注。但是，单分子人工通道的结构比较复杂，如何通过共价合成高效构筑长度足以穿透脂双层的管状分子成为该研究领域的难点。本项目以大环-多肽分子为骨架，利用一步成环法以及click反应等共价合成策略高效构筑了一系列具有高结构稳定性、高选择性以及传输效率的单分子人工跨膜离子通道。项目组通过控制通道结构实现了人工钾离子通道、pH响应性人工跨膜通道以及高阳离子选择性人工跨膜通道的构筑，并发展了一类具有高抗菌性和低溶血毒性的单分子人工跨膜通道。本项目的研究对建立新的人工跨膜输送体系设计思路，发展功能化人工跨膜通道提供了有价值的理论依据和技术支持。