Laboratory of Molecular Nutrition and Immunity. The Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, P. R. China.
J Med Chem. 2020 Sep 10;63(17):9421-9435. doi: 10.1021/acs.jmedchem.0c00583. Epub 2020 Aug 10.
Antimicrobial peptides (AMPs) are expected to solve problem of antibiotic resistance because of their distinctive nonspecific membrane-disruptive mechanism. However, clinical applications of AMPs have been precluded by their poor stability, although various complex chemical strategies have been employed to solve this problem, and this undoubtedly greatly increases the manufacturing cost. Herein, a series of novel peptides with high stability were developed based on protease-specific cleavage sites and symmetrical end-tagging. Among these peptides, II-I-II exhibited the best antibacterial activity and the highest therapeutic index. More importantly, II-I-II showed extremely high stability in the presence of various proteases, physiological salts and serum, and under acid, alkali, and heat conditions, and it exhibited excellent therapeutic potential . Additionally, II-I-II exhibited a membrane-disruptive mechanism and a low propensity to induce resistance. In general, these findings contribute to the design of AMPs with high stability and might accelerate clinical applications of AMPs.
抗菌肽（AMPs）因其独特的非特异性膜破坏机制而有望解决抗生素耐药性问题。然而，尽管采用了各种复杂的化学策略来解决这个问题，但 AMPs 的临床应用仍然受到其稳定性差的限制，这无疑大大增加了制造成本。在此，基于蛋白酶特异性切割位点和对称端标记，开发了一系列具有高稳定性的新型肽。在这些肽中，II-I-II 表现出最好的抗菌活性和最高的治疗指数。更重要的是，II-I-II 在存在各种蛋白酶、生理盐和血清以及在酸、碱和热条件下表现出极高的稳定性，并且具有优异的治疗潜力。此外，II-I-II 表现出膜破坏机制和低诱导耐药倾向。总的来说，这些发现有助于设计具有高稳定性的 AMP，并可能加速 AMP 的临床应用。
