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. WK<sub>2</sub> (GWWKKWWKKI-NH<sub>2</sub>) 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 WK<sub>2</sub> 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 WK<sub>2</sub> analogs were systematically evaluated, and their structure-activity relationships were studied. Compared with WK<sub>2</sub>, 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 WK<sub>2</sub>. 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.
Authors
- Zufang Ba
- Xueting Liu
- Lanqing Hu
- Pengyi Yan (ORCID: https://orcid.org/0000-0002-4038-3283)
- Bingqian Ren
- Sanhu Gou (ORCID: https://orcid.org/0000-0003-3231-7427)
- Jingman Ni (ORCID: https://orcid.org/0000-0002-8728-1268)
- Xu Ouyang
- Yun Zhang (ORCID: https://orcid.org/0000-0002-4262-5354)
- Yu Wang (ORCID: https://orcid.org/0000-0002-8098-2491)
- Beibei Li (ORCID: https://orcid.org/0009-0007-0143-300X)
- Jie Liu (ORCID: https://orcid.org/0000-0002-3849-6414)
- Yao Liu (ORCID: https://orcid.org/0000-0001-6750-9950)
- Hui Liu (ORCID: https://orcid.org/0009-0005-8690-141X)
- Jingying Zhang (ORCID: https://orcid.org/0000-0002-6503-0767)
- Yuan Li (ORCID: https://orcid.org/0000-0003-4352-4616)
- Qingyang Xu (ORCID: https://orcid.org/0000-0003-1619-3508)
- Chao Zhong (ORCID: https://orcid.org/0000-0001-5975-9925)
- Tingting Yang (ORCID: https://orcid.org/0000-0003-0366-4307)
- Zhongwei Yu (ORCID: https://orcid.org/0000-0002-8152-0889)
Institutions
- Macau University of Science and Technology (MO)
- Jinan University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Laboratoire de Chémo-biologie synthétique et thérapeutique (FR)
- Lanzhou University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00922
- Citations
- 3
- Primary Topic
- Antimicrobial Peptides and Activities
- Type
- article
- Field-Weighted Citation Impact
- 3.55