Discovery of Guanidyl-Stapled Aurein1.2 Peptides with Potent In Vivo Antimicrobial Activities

Antimicrobial peptides (AMPs), distinguished by their broad-spectrum antibacterial activity and low propensity to induce antibiotic resistance, show the promising potential for infectious diseases. However, the direct development of AMPs into therapeutics remains challenging due to their poor proteolytic stability and limited in vivo antibacterial activity. This study employed our pioneering solid-phase and side-chain guanidyl-construction (SSG) stapling technique to systematically screen and modify the natural AMP Aurein1.2, resulting in a series of guanidyl-stapled peptides A1 to A9. The optimal guanidyl-stapled peptide A4 exhibited the significantly improved α-helical content and proteolytic stability than the linear counterpart, as well as potent in vitro antibacterial activity and acceptable hemolysis. Importantly, A4 demonstrated markedly enhanced therapeutic performance for the treatment of the Staphylococcus aureus infected wound on mice, highlighting its strong potential as the next-generation antimicrobial agent.