As an evolutionarily conserved family of antimicrobial peptides (AMPs), cecropins play an important role in innate immunity. But their inevitable weaknesses, including poor proteolytic stability and unpredictable cytotoxicity, severely hindered their clinical applications. Considering their two-helical structure, all-hydrocarbon stapling was performed on cecropin A, successfully generating 27 (, + 4) stapled derivatives. By evaluating antimicrobial and hemolytic activities, CEC-2-9 with the -terminus threonine and lysine being stapled was identified as the optimal one. It exerted significantly enhanced antibacterial potency with more severe bacterial membrane damage capacity. Compared to cecropin A, its increased helicity and hydrophobicity as well as the decreased net charge also enabled its improved stability and biocompatibility, facilitating its enhanced antibacterial and anti-inflammatory efficacy for the effective treatment of mice with peritonitis sepsis. These results have proven that the systematic all-hydrocarbon stapling of AMPs was a feasible approach for the future development of antibacterial therapeutics.
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