本项目拟采用同步提高α-螺旋型抗菌肽构象稳定性和酶解稳定性的组合策略对母肽进行结构改造。采用click reaction产生的三唑链接子在活性抗菌肽分子内和分子间进行桥化连接，通过不同桥化位点和长度的设计，探索其最佳桥化位点和该策略能否像“别针”一样起到固定α-螺旋肽类抗菌肽Anoplin空间构象，进而增加其生物膜穿透作用，达到增强其结构稳定性，提高活性和生物利用度作用。同时，采用非天然氨基酸改造策略，通过对母肽构效关系研究，探索在不改变其原有的净电荷数、肽链长度或者完整性，最大限度保持其原有活性的前提下，分别从其疏水面和亲水面出发设计非天然氨基改造位点，提高其抗酶解稳定性。通过对新设计、合成抗菌肽类似物进行抗菌活性，二维立体空间结构，安全性，酶解稳定性等方面进行系统构效关系研究，评价该组合策略在抗菌肽稳定性改造方面的作用效果，为最终推进抗菌肽类药物临床应用瓶颈问题的解决做出努力。

This project intends to use combining strategies to study the stabilization effective for α-spiral antimicrobial peptides. One of it is use intramolecular and intermolecular chain link with a triazole bridge to reinforce the molecular conformation stabilization of natural α-spiral antimicrobial peptides Anoplin. And the other one is to reconstitute Anoplin with unnatural amino acids on its key enzymatic degradation point, without changes its net charge, chain length and integrality. In hoping of reinforce both molecular conformation and enzymatic stabilization at the same time. The study will provide research basis for developing a new peptide stabilized strategy and find new antimicrobial peptides drugs which have high antimicrobial activity and high stability for clinical application.