Systematic All-Hydrocarbon Stapling Analysis for Cecropin A Generates a Potent and Stable Antimicrobial Peptide

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 (i, i + 4) stapled derivatives. By evaluating antimicrobial
and hemolytic activities, CEC-2–9 with the C-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.