Antimicrobial peptides (AMPs) are regarded as promising candidates for combating antimicrobial resistance. Previously we identified an AMP named Cm-CATH2 from the green sea turtle, which exhibited potent antibacterial activity and attractive potential in application. However, natural AMPs including Cm-CATH2 frequently suffer from structural instability and sensitivity to physiological conditions, limiting their effectiveness. Herein, we explored various strategies to enhance the efficacy and stability of Cm-CATH2, including peptide truncation, non-natural amino acid substitutions, disulfide bond-based cyclization, and stapled peptide techniques. The results demonstrated that the truncated NCM4 significantly improved the antimicrobial capability of Cm-CATH2 while also enhancing its anti-inflammatory and antibiofilm activities with minimal cytotoxicity. Further ornithine-substituted peptide oNCM markedly enhanced the stability of NCM4 without compromising its antimicrobial efficacy. This study successfully designed a lead peptide oNCM with significant development potential, while providing valuable insights into the advantages and limitations associated with diverse strategies for enhancing the stability of AMPs.

中文翻译：

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使用多种结构修饰策略提高海龟 AMPs 的稳定性和抗感染活性


抗菌肽 （AMP） 被认为是对抗抗菌素耐药性的有前途的候选者。以前我们从绿海龟中鉴定出一种名为 Cm-CATH2 的 AMP，它表现出强大的抗菌活性和诱人的应用潜力。然而，包括 Cm-CATH2 在内的天然 AMP 经常存在结构不稳定和对生理条件敏感的问题，限制了它们的有效性。在此，我们探索了提高 Cm-CATH2 疗效和稳定性的各种策略，包括肽截断、非天然氨基酸取代、基于二硫键的环化和装订肽技术。结果表明，截短的 NCM4 显著提高了 Cm-CATH2 的抗菌能力，同时还增强了其抗炎和抗生物膜活性，细胞毒性最小。进一步的鸟氨酸取代肽 oNCM 显着增强了 NCM4 的稳定性，而不会影响其抗菌功效。本研究成功设计了具有巨大开发潜力的先导肽 oNCM，同时为增强 AMP 稳定性的各种策略的优势和局限性提供了有价值的见解。