Yao Aifang, Zhang Zeyu, Song Zhengmin, Yuan Yi, Chen Xiaoling, Ma Chengbang, Chen Tianbao, Shaw Chris, Zhou Mei, Wang Lei
College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China.
Engineering and Technology Institute Groningen, Faculty of Science and Engineering, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
Antibiotics (Basel). 2025 Aug 1;14(8):784. doi: 10.3390/antibiotics14080784.
: The clinical potential of antimicrobial peptides (AMPs) against dual threats like antimicrobial resistance (AMR) and cancer is often limited by their high host cell toxicity. Here, we focused on brevinin-2OS (B2OS), a novel peptide from the skin of with potent haemolytic activity. The objective was to study the structure-activity relationship and optimise the safety via targeted modifications. A dual-modification strategy involving C-terminal truncation and subsequent N-terminal D-amino acid substitution was employed. The bioactivities and safety profiles of the resulting analogues were evaluated using antimicrobial, haemolysis, and cytotoxicity assays. Removal of the rana box in B2OS(1-22)-NH substantially reduced haemolysis while maintaining bioactivities. Remarkably, the D-leucine substitution in [D-Leu]B2OS(1-22)-NH displayed a superior HC value of 118.1 µM, representing a more than ten-fold improvement compared to its parent peptide (HC of 10.44 µM). This optimised analogue also demonstrated faster bactericidal kinetics and enhanced membrane permeabilisation, leading to a greater than 22-fold improvement in its therapeutic index against Gram-positive bacteria. The C-terminal rana box is a primary determinant of toxicity rather than a requirement for activity in the B2OS scaffold. The engineered peptide [D-Leu]B2OS(1-22)-NH emerges as a promising lead compound, and this dual-modification strategy provides a powerful design principle for developing safer, more effective peptide-based therapeutics.
抗菌肽（AMPs）对抗抗菌耐药性（AMR）和癌症等双重威胁的临床潜力常常受到其对宿主细胞高毒性的限制。在此，我们聚焦于brevinin-2OS（B2OS），一种来自皮肤的具有强大溶血活性的新型肽。目的是研究构效关系并通过靶向修饰优化安全性。采用了一种涉及C端截短和随后N端D-氨基酸取代的双重修饰策略。使用抗菌、溶血和细胞毒性测定评估所得类似物的生物活性和安全性概况。在B2OS(1 - 22)-NH中去除蛙皮盒可大幅降低溶血，同时保持生物活性。值得注意的是，[D-Leu]B2OS(1 - 22)-NH中的D-亮氨酸取代显示出118.1 μM的优异HC值，与其亲本肽（HC为10.44 μM）相比提高了十多倍。这种优化的类似物还表现出更快的杀菌动力学和增强的膜通透性，导致其对革兰氏阳性菌的治疗指数提高了22倍以上。C端蛙皮盒是毒性的主要决定因素，而非B2OS支架中活性的必需条件。工程肽[D-Leu]B2OS(1 - 22)-NH成为一种有前景的先导化合物，这种双重修饰策略为开发更安全、更有效的基于肽的治疗方法提供了有力的设计原则。
