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.