Due to the alarming developing rate of multidrug-resistant bacterial pathogens, the development and modification of antimicrobial peptides (AMPs) are unprecedentedly active. Despite the fact that considerable efforts have been expended on the discovery and design strategies of AMPs, the clinical translation of peptide antibiotics remains inadequate. A large number of articles and reviews credited the limited success of AMPs to their poor stability in the biological environment, particularly their poor proteolytic stability. In the past forty years, various design strategies have been used to improve the proteolytic stability of AMPs, such as sequence modification, cyclization, peptidomimetics, and nanotechnology. Herein, we focus our discussion on the progress made in improving the proteolytic stability of AMPs and the principle, successes, and limitations of various anti-proteolytic design strategies. It is of prospective significance to extend current insights into the degradation-related inactivation of AMPs and also alleviate/overcome the problem.

由于多重耐药细菌病原体的惊人发展速度，抗菌肽（AMPs）的开发和修饰空前活跃。尽管在 AMP 的发现和设计策略上付出了相当大的努力，但肽类抗生素的临床转化仍然不足。大量文章和评论将 AMP 的有限成功归因于它们在生物环境中的稳定性差，特别是它们的蛋白水解稳定性差。在过去的四十年中，各种设计策略已被用于提高 AMP 的蛋白水解稳定性，例如序列修饰、环化、肽模拟物和纳米技术。在此，我们将重点讨论在提高 AMP 蛋白水解稳定性方面取得的进展以及原理、成功、和各种抗蛋白水解设计策略的局限性。将当前的见解扩展到与降解相关的 AMP 失活并缓解/克服该问题具有前瞻性意义。