School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, People's Republic of China.
Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China.
J Med Chem. 2022 Aug 11;65(15):10523-10533. doi: 10.1021/acs.jmedchem.2c00661. Epub 2022 Aug 3.
Antimicrobial peptides (AMPs) have attracted great attention as next generation antibiotics for the treatment of multidrug-resistant (MDR) bacterial infections. Poor proteolytic stability has however undermined clinical applications of AMPs. A novel peptide cyclization approach is described to enhance the antibacterial activity of AMPs. Bicyclic antimicrobial peptides were synthesized by cross-linking the ε-amino groups of three lysine residues with a 1,3,5-trimethylene benzene spacer. In a proof of principal study, four bicyclic peptides were synthesized from the cationic AMP OH-CM6. One bicyclic peptide retained strong antimicrobial activity and low toxicity but exhibited a prolonged half-life in serum. Antibacterial activity was consequently improved without renal or hepato-toxicity. The novel peptide cyclization approach represents an important tool for enhancing AMP proteolytic stability for improved treatment of bacterial infection.
抗菌肽 (AMPs) 作为治疗多重耐药 (MDR) 细菌感染的下一代抗生素受到了极大的关注。然而，较差的蛋白水解稳定性阻碍了 AMPs 的临床应用。本文描述了一种新的肽环化方法来增强 AMPs 的抗菌活性。通过交联三个赖氨酸的 ε-氨基与 1,3,5-三甲叉苯间隔物，合成了双环抗菌肽。在一个原理验证研究中，从阳离子 AMP OH-CM6 合成了四个双环肽。一个双环肽保留了很强的抗菌活性和低毒性，但在血清中的半衰期延长。抗菌活性因此得到改善，同时没有肾毒性或肝毒性。该新的肽环化方法为提高 AMP 的蛋白水解稳定性提供了一种重要的工具，以改善细菌感染的治疗效果。
