新型阳离子桥联抗菌肽的合成及其抗炎症作用研究

广泛存在的细菌多药耐药性问题，使得发展新型抗生素的需求迫切。抗菌肽是一类具有广谱抗菌活性及免疫调节活性的内源性多肽，是发展新型抗生素的优良前体。我们前期研究发现，通过引入赖氨酸侧链交联的阳离子桥联订书针结构修饰抗菌肽，可以提高抗菌肽的蛋白酶稳定性，同时抑制溶血毒性，因此，阳离子桥联修饰对于发展基于抗菌肽的新型抗生素是一种具有重大潜力的新策略。本项目基于前期研究成果，拟进一步通过阳离子订书针结构插入位点筛选、订书针连接结构优化、引入双订书针结构等途径优化阳离子桥联抗菌肽的结构，筛选出具有良好抗菌活性、高蛋白酶稳定性及低溶血毒性的候选化合物，深入研究其抗炎症作用及免疫调解作用，并利用败血症小鼠模型评价其治疗作用，推动基于阳离子桥联抗菌肽的新型抗生素开发向临床前研究发展。

Because of the widely spread of multi-drug resistant bacteria, the need for development of novel antibiotics is urgent. Antimicrobial Peptides are one class of important endogenous peptides with broad antibacterial activity and immunomodulating activity, which made them excellent candidates for developing novel antibiotics. Our previous research found that introduction of a cation-bridged staple structure by cross-linking of sidechain of lysine can increase protease stability and inhibit hemolysis of antimicrobial peptide. Therefore, modification of antimicrobial peptide with cationic staple structure is potentially an important strategy for developing novel antibiotics based on antimicrobial peptide. Based on these results，it is the purpose of this project to further optimization of cation-bridged antimicrobial by screening the position of staple structure, optimizing the structure of the linker and introduction of double-staple structure. By biological activity screening, we hope to find novel cation-bridged antimicrobial peptides with high protease stability, low hemolysis and excellent antibacterial activity. Furthermore, we will explore the anti-inflammatory and immunomodulating activity of the cation-bridged antimicrobial peptide and evaluate its therapeutic potential for sepsis using mouse model. With the results of this project, our goal is to promote the development of novel antibiotics based on cation-bridged antimicrobial peptide toward pre-clinical study.