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

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.