Yan Xi, Yang Chengyi, Li Bo, Bian Yifeng, Yu Weikang, Zhu Yongjie, Cheng Baojing, Lyu Yinfeng, Shan Anshan
College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, People's Republic of China.
J Med Chem. 2025 Jan 23;68(2):1397-1416. doi: 10.1021/acs.jmedchem.4c01966. Epub 2025 Jan 1.
Antimicrobial peptides (AMPs) show potential as antibiotic alternatives for bacterial infections; nevertheless, the susceptibility to proteases limits their broader utilization. This study developed engineered lipopeptides using antienzymolysis modifications and cysteine (Cys)-dimerization strategy. As the key parameters for the functioning of AMPs, hydrophobicity and positive charges were concentrated within the peptide sequence by adjusting the intermolecular disulfide bond placement to study their distribution effects. Their centralization in the sequence induces a differential propensity of engineered lipopeptides toward bacterial membranes. Positive charge-concentrated dimeric lipopeptide (C-C) displayed strong resistance to various proteases, and demonstrated excellent stability and activity , effectively eliminating systemic bacterial infections in mice without eliciting toxicity. The bactericidal effects of (C-C) were achieved through a synergistic mechanism involving membrane cleavage and the inhibition of energy metabolism. In summary, these advances offered valuable insights into enhancing the protease resistance of AMPs and the potential for modifying peptide-based biomaterials through Cys-dimerization.
抗菌肽（AMPs）作为细菌感染抗生素替代品具有潜力；然而，其对蛋白酶的敏感性限制了它们的广泛应用。本研究采用抗酶解修饰和半胱氨酸（Cys）二聚化策略开发了工程化脂肽。作为抗菌肽发挥功能的关键参数，疏水性和正电荷通过调整分子间二硫键位置集中在肽序列内，以研究它们的分布效应。它们在序列中的集中诱导了工程化脂肽对细菌膜的不同倾向。正电荷集中的二聚体脂肽（C-C）对各种蛋白酶表现出强大抗性，并显示出优异的稳定性和活性，能有效消除小鼠全身细菌感染且不引发毒性。（C-C）的杀菌作用是通过涉及膜裂解和能量代谢抑制的协同机制实现的。总之，这些进展为增强抗菌肽的蛋白酶抗性以及通过Cys二聚化修饰基于肽的生物材料的潜力提供了有价值的见解。
