All‐hydrocarbon stapling enables improvement of antimicrobial activity and proteolytic stability of peptide Figainin 2

Figainin 2 is a cationic, hydrophobic, α‐helical host‐defense peptide with 28 residues, which was isolated from the skin secretions of the Chaco tree frog. It shows potent inhibitory activity against both Gram‐negative and Gram‐positive pathogens and has garnered considerable interest in developing novel classes of natural antibacterial agents. However, as a linear peptide, conformational flexibility and poor proteolytic stability hindered its development as antibacterial agent. To alleviate its susceptibility to proteolytic degradation and improve its antibacterial activity, a series of hydrocarbon‐stable analogs of Figainin 2 were synthesized and evaluated for their secondary structure, protease stability, antimicrobial, and hemolytic activities. Among them, F2‐12 showed significant improvement in protease resistance and antimicrobial activity compared to that of the template peptide. This study provides a promising strategy for the development of antimicrobial drugs.