Synthesis of antibacterial pseudopeptides with less hemolytic activity from a cytotoxic peptide and their pH-dependent activity.

We synthesized antibacterial pseudopeptides with less hemolytic activity by incorporation of reduced amide bond psi[CH2NH] into alpha helical antibacterial peptide with hemolytic activity. As the pKa value of reduced amide bond is 7-8, it is protonated depending on the pH. We investigated the secondary structure, the binding affinity and the leakage activity for the vesicles, and the antibacterial activity of the peptide and its pseudopeptides at neutral and basic pH. Unlike the peptide, the pseudopeptides showed a more potent leakage activity when pH increased. The peptide exhibited a lower antibacterial activity at basic pH than at neutral pH, whereas the pseudopeptide showed the same antibacterial activity at basic and neutral pH. Overall results indicated that hydrophobicity of backbone of the pseudopeptide plays an important role in the increase of leakage activity and retention of antibacterial activity at basic pH.