氟化修饰是一种有效提高抗菌肽稳定性和活性的简单策略。

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-09-28 DOI:10.1021/acs.jmedchem.5c00922

Xu Ouyang,Liru Yuan,Tingting Yang,Qingyang Xu,Beibei Li,Jingying Zhang,Jie Liu,Lanqing Hu,Zufang Ba,Yao Liu,Yu Wang,Zhongwei Yu,Pengyi Yan,Bingqian Ren,Xueting Liu,Chao Zhong,Hui Liu,Yun Zhang,Sanhu Gou,Jingman Ni

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引用次数: 0

摘要

抗菌肽是一种很有发展前景的抗菌药物；然而，它们的问题，如蛋白水解降解和非特异性毒性，阻碍了它们的临床应用。WK2 （GWWKKWWKKI-NH2）是我们在前期研究中筛选出的抗菌性能较好的AMP。但稳定性差。本研究在计算机预测WK2蛋白水解裂解位点的基础上，利用非天然氨基酸对其序列进行修饰。系统评价了新的WK2类似物的酶解稳定性、抗菌活性和细胞毒性，并研究了它们的构效关系。与WK2相比，其氟肽类似物FuK具有优异的抗菌性能。特别是，FuK的血清半衰期超过1440 min，至少是WK2的6.4倍。在体内，FuK表现出良好的安全性和治疗效果。综上所述，氟化修饰可能是一种很有前途的策略，可以有效地提高新型抗菌肽的抗菌性能和稳定性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Fluorinated Modification as a Simple Strategy That Effectively Enhances the Stability and Activity of Antimicrobial Peptides.

Antimicrobial peptides (AMPs) are promising antibacterial agents; however, their issues, such as proteolytic degradation and nonspecific toxicity, hinder their clinical application. WK2 (GWWKKWWKKI-NH2) is an AMP with a good antimicrobial performance, which was screened out in our previous study. However, it has poor stability. In this study, the sequence of WK2 was modified with unnatural amino acids based on predicting its proteolytic cleavage sites by computer. The enzymatic hydrolysis stability, antimicrobial activity, and cytotoxicity of the new WK2 analogs were systematically evaluated, and their structure-activity relationships were studied. Compared with WK2, its fluoropeptide analogue, FuK, exhibits excellent antibacterial properties. In particular, the serum half-life of FuK exceeds 1440 min, which is at least 6.4-fold that of WK2. In vivo, FuK demonstrated excellent safety and therapeutic efficacy. In conclusion, fluorination modification may be a rather promising strategy that can effectively enhance the antimicrobial properties and stability of the new AMPs.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.