Zhang Jingying, Chu Anqi, Ouyang Xu, Li Beibei, Yang Ping, Ba Zufang, Yang Yinyin, Mao Wenbo, Zhong Chao, Gou Sanhu, Zhang Yun, Liu Hui, Ni Jingman
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou, 730000, PR China.
Institute of Pharmaceutics, School of Pharmacy, 2019RU066, Lanzhou University, Lanzhou, 730000, PR China.
Eur J Med Chem. 2025 Mar 15;286:117310. doi: 10.1016/j.ejmech.2025.117310. Epub 2025 Jan 23.
De novo design of antimicrobial peptides is a pivotal strategy for developing new antibacterial agents, leveraging its rapid and efficient nature. (XXYY), where X represents cationic residues, Y denotes hydrophobic residues, and n varies from 2 to 4, is a classical α-helix template. Based on which, numerous antimicrobial peptides have been synthesized. Herein, we hypothesize that the amphipathy of this type of α-helix template can be further enhanced based on the principles of α-helical protein folding, characterized by a rotation occurring every 3.6 amino acid residues, and propose the highly amphipathic template XXYYXXYXXYYX (where X represents cationic residues and Y denotes hydrophobic residues). Accordingly, the amino acid composition and arrangement of the α-helix peptide (RRWF) are adjusted, yielding the highly amphipathic counterpart H-R (RRWFRRWRRWFR). The structure-activity relationship of which is further explored through the substitution of residues at positions 8 and 12. Notably, the highly amphipathic peptides exhibit enhanced antimicrobial activity and reduced hemolytic toxicity compared to (RRWF), resulting in superior bacterial selectivity. The most highly amphipathic peptide, H-R, demonstrates potent activity against biofilms and multidrug-resistant bacteria, low propensity for resistance, and high safety and effectiveness in vivo. The antibacterial mechanisms of H-R are also preliminarily investigated in this study. As noted, H-R represents a promising antimicrobial candidate for addressing infections associated with drug-resistant bacteria.
抗菌肽的从头设计是开发新型抗菌剂的关键策略，因其具有快速高效的特性。（XXYY）是一种经典的α-螺旋模板，其中X代表阳离子残基，Y表示疏水残基，n取值范围为2至4。基于此，人们合成了许多抗菌肽。在此，我们假设基于α-螺旋蛋白折叠原理（其特征是每3.6个氨基酸残基发生一次旋转），这种类型的α-螺旋模板的两亲性可以进一步增强，并提出了高度两亲的模板XXYYXXYXXYYX（其中X代表阳离子残基，Y表示疏水残基）。相应地，调整了α-螺旋肽（RRWF）的氨基酸组成和排列，得到了高度两亲的对应物H-R（RRWFRRWRRWFR）。通过替换第8位和第12位的残基进一步探索了其构效关系。值得注意的是，与（RRWF）相比，高度两亲的肽表现出增强的抗菌活性和降低的溶血毒性，从而具有更高的细菌选择性。高度两亲性最强的肽H-R对生物膜和多重耐药菌表现出强大的活性，耐药倾向低，在体内具有高安全性和有效性。本研究还初步探究了H-R的抗菌机制。如前所述，H-R是一种有前景的抗菌候选物，可用于解决与耐药菌相关的感染问题。
