| Summary: | Magainin 2 (<b>Mag2</b>), which was isolated from the skin of the African clawed frog, is a representative antimicrobial peptide (AMP) that exerts antimicrobial activity via microbial membrane disruption. It has been reported that the helicity and amphipathicity of <b>Mag2</b> play important roles in its antimicrobial activity. We investigated and recently reported that 17 amino acid residues of <b>Mag2</b> are required for its antimicrobial activity, and accordingly developed antimicrobial foldamers containing α,α-disubstituted amino acid residues. In this study, we further designed and synthesized a set of <b>Mag2</b> derivatives bearing the hydrocarbon stapling side chain for helix stabilization. The preferred secondary structures, antimicrobial activities, and cell-membrane disruption activities of the synthesized peptides were evaluated. Our analyses revealed that hydrocarbon stapling strongly stabilized the helical structure of the peptides and enhanced their antimicrobial activity. Moreover, peptide <b>2</b> stapling between the first and fifth position from the <i>N</i>-terminus showed higher antimicrobial activity than that of <b>Mag2</b> against both gram-positive and gram-negative bacteria without exerting significant hemolytic activity. To investigate the modes of action of tested peptides <b>2</b> and <b>8</b> in antimicrobial and hemolytic activity, electrophysiological measurements were performed.
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