Insights into the Antimicrobial Activity and Cytotoxicity of Engineered α‑Helical Peptide Amphiphiles

Antimicrobial peptides (AMPs) have
gained increasing attention,
as they can overcome recurring microbial invasions. However, their
poor antimicrobial activity and potential cytotoxicity remain impediments
to their clinical applications as novel therapeutic agents. To enhance
the antimicrobial activity and cell selectivity of AMPs, a series
of amphiphilic peptides based on leucocin A were designed by substituting
noncharged hydrophilic residues with arginine and leucine. Of the
engineered peptides, peptide 7 (WRL3) (WLRAFR­RLVRRL­ARGLRR-NH2)
exhibited the highest cell selectivity toward bacterial cells over
erythrocytes and macrophages. Fluorescent measurements and microscopic
observations demonstrated that 7 increased cell membrane
permeability and disrupted membrane envelope integrity, and eventually
led to whole cell lysis. Additionally, flow cytometry analysis and
subcellular localization studies revealed that 7 showed
potent cytotoxicity against human hepatoma cells HepG2. In summary,
the data indicate that these engineered peptides, in particular 7, have enormous promise for antibacterial and/or antitumor
therapeutics.