Effect of amino acid substitution in amphiphilic α-helical peptides on peptide-phospholipid membrane interaction

It was previously found that a cationic amphiphilic peptide, Ac-(Leu-Ala-Arg-Leu)(3)-NHCH3 (4(3)), caused the destabilization of a phospholipid membrane and showed strong antibacterial activity [Lee et al. Biochim. Biophys. Acta 1986; 862: 211-219]. In order to investigate the effect of changing alpha-helix propensity, hydrophobicity and basicity in 4(3) on the peptide conformation and activity, the 4(3) analogs, [Gly (or Val)(6)]4(3), [Gly (or Val)(2.6)]4(3), [Gly (or Val)(2.6.10)]4(3), [Gln(3)]4(3), [Gln(3.7)]4(3) and [Gln(3.7.11)]4(3) were synthesized. Except for [Val(2.6)]4(3) and [Val(2.6.10)]4(3), which mainly formed a beta-structure, other peptides formed an alpha-helix and showed moderate membrane-perturbing activity toward neutral and acidic lipid vesicles. All the peptides other than [Val(2.6.10)]4(3) and [Gln(3.7.10)]4(3) had the antibacterial activity comparable with that of 4(3). The relationship between the membrane-perturbing activity and the antibacterial activity was not always parallel. Conclusively, the Ala --> Val substitution in 4(3) causes the change of peptide conformation and the presence of a cationic amino acid residue is necessary for the antibacterial activity. Copyright (C) 1999 European Peptide Society and John Wiley & Sons, Ltd.