Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity

G(IIKK)3I-NH2 has been recently shown to be highly effective at killing bacteria and inhibiting cancer cell growth while remaining benign to normal host mammalian cells. The aim of this work is to evaluate how residue substitutions of Ala (A), Val (V), Glu (E), and Lys (K) for the N-terminal Gly (G) or C-terminal Ile (I) of G(IIKK)3I-NH2 affect the physiochemical properties and bioactivity of the variants. All substitutions caused the reduction of peptide hydrophobicity, while N-terminal substitutions had a less noticeable effect on the surface activity and helix-forming ability than C-terminal substitutions. N-terminal variants held potent anticancer activity but exhibited reduced hemolytic activity; these actions were related to the maintenance of their moderate surface pressures (12–16 mN m–1), while their hydrophobicity was reduced. Thus, N-terminal substitutions enhanced the cell selectivity of the mutants relative to the control peptide G(IIKK)3I-NH2. In contrast, C-terminal variants exhibited lower...