Phosphorylation as an Effective Tool to Improve Stability and Reduce Toxicity of Antimicrobial Peptides

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-10-09 DOI:10.1021/acs.jmedchem.4c01179

Zufang Ba, Yu Wang, Yinyin Yang, Bingqian Ren, Beibei Li, Xu Ouyang, Jingying Zhang, Tingting Yang, Yao Liu, Yuhuan Zhao, Ping Yang, Xiaoyan Wu, Wenbo Mao, Chao Zhong, Hui Liu, Yun Zhang, Sanhu Gou, Jingman Ni

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Abstract

Developing a straightforward and effective strategy to modify antimicrobial peptides (AMPs) is crucial in overcoming the challenges posed by their instability and toxicity. Phosphorylation can reduce toxicity and improve the stability of AMPs. Based on these, we designed a series of peptides and their corresponding phosphorylated forms. The results showed that all phosphorylated peptides displayed reduced toxicity and enhanced stability compared to their unphosphorylated counterparts. Among them, W₃BipY₈-P stood out as the most promising peptide, exhibiting similar antibacterial activity as its unphosphorylated analog W₃BipY₈ but with significantly reduced hemolytic activity (19-fold decrease), cytotoxicity (3.3-fold decrease), and an extended serum half-life 6.3 times longer than W₃BipY₈. W₃BipY₈-P exerted bactericidal effects by disrupting bacterial membranes. Notably, W₃BipY₈-P significantly prolonged the survival of bacteria-infected animals while its LD₅₀ was 4.2 times higher than that of W₃BipY₈. These findings highlight phosphorylation as an effective strategy for improving the antimicrobial properties of AMPs.

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磷酸化是提高抗菌肽稳定性和降低其毒性的有效工具

要克服抗菌肽（AMPs）的不稳定性和毒性所带来的挑战，开发一种直接有效的策略来修饰抗菌肽（AMPs）至关重要。磷酸化可以降低抗菌肽的毒性并提高其稳定性。在此基础上，我们设计了一系列肽及其相应的磷酸化形式。结果表明，与未磷酸化的对应物相比，所有磷酸化肽都显示出毒性降低和稳定性增强的特点。其中，W3BipY8-P 是最有前途的多肽，其抗菌活性与其未磷酸化类似物 W3BipY8 相似，但溶血活性（降低了 19 倍）和细胞毒性（降低了 3.3 倍）显著降低，血清半衰期比 W3BipY8 延长了 6.3 倍。W3BipY8-P 通过破坏细菌膜发挥杀菌作用。值得注意的是，W3BipY8-P 能显著延长受细菌感染动物的存活时间，而其半数致死剂量是 W3BipY8 的 4.2 倍。这些发现突出表明，磷酸化是提高 AMP 抗菌特性的一种有效策略。

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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.