Structure–Activity Relationship Study of Helix-Stabilized Antimicrobial Peptides Containing Nonproteinogenic Amino Acids

Abstract

Helical amphipathic peptides containing cationic and hydrophobic amino acid residues can possess potent antimicrobial activity against both Gram-positive and Gramnegative bacteria. In this study, several amphipathic peptides with enhanced helical structures containing nonproteinogenic amino acids were designed, and the relationships between the antimicrobial activity, hemolytic activity, and cytotoxicity were evaluated. In particular, the effect on the antimicrobial activity and cytotoxicity of the number and position of stapling structures introduced into the sequence was investigated. Peptide stp1 containing α,α-disubstituted amino acids showed potent antimicrobial activity against multidrug-resistant bacteria (MDRP, SP45, and Staphylococcus aureus) without causing appreciable hemolytic activity or cytotoxicity. The cytotoxicity was found to be somewhat correlated to the hydrophobicity of the peptides.