有机电化学合成实现环肽构建及其在蛋白质修饰中的应用

多肽类化合物是一类备受重视的生物治疗药物，然而因膜通透性差、代谢稳定性低和对蛋白酶敏感等固有特性，导致其在临床治疗中的应用相当受限。实现多肽的环化能有效地解决上述难题。但目前已发展的多肽环化策略通常依赖于需多步合成的非天然氨基酸序列，而基于天然氨基酸的环化反应十分有限。另外，电化学近年来发展迅速，被广泛运用于有机合成，具有绿色、高效和高选择性等优点。但能在生物兼容条件下，运用电化学实现生物分子修饰的报道寥寥无几，其中电化学实现多肽的环化更是未有文献报道。由此，本项目力图在生物兼容条件下建立新型的电化学体系，实现以线性多肽上天然氨基酸为靶点的高选择性环化反应，并运用于蛋白质的选择性修饰。本项目的开展可实现有机方法学与化学生物学的交叉融合，发展温和、简易、高效的生物活性分子修饰与改性的方法，有望为多肽类药物的开发研究提供新的策略。

Peptides are emerging as an important class of biological therapeutic drugs which have attracted extensive attention in the fields of medicine, biology and chemistry. However, the application of linear peptides as clinic drugs is strongly hindered by their inherent characteristics, such as poor membrane permeability, low metabolic stability and sensitivity to protease. These shortcomings can be effectively overcome by peptide macrocyclization reactions. Well-developed macrocyclization methods usually rely on unnatural amino acid sequences which were synthesized by multistep strategies, and it is still difficult to realize a macrocyclization strategy based on natural amino acid residues. In addition, characterized by high efficiency and selectivity, electrochemistry has been widely used in organic synthesis in recent years. However, there are only few reports that can achieve the electrochemical modifications of biomolecules under biocompatible conditions, and the electrochemical cyclization of peptides hasn’t been reported. Hence, this project aims to establish a novel electrochemical system with biocompatibility, enabling the selective macrocyclization of linear peptides based on natural amino acids, and the specific modification of proteins. Furthermore, this project can realize the cross integration of organic methodology and chemical biology, and develop mild and efficient methods for the modification of bioactive molecules, which is expected to provide new access to novel peptide drugs.