Therapeutic Potential of Trp-Rich Engineered Amphiphiles by Single Hydrophobic Amino Acid End-Tagging.

End-tagging with a single hydrophobic residue contributes to improve the cell selectivity of antimicrobial peptides (AMPs), but systematic studies have been lacking. Thus, this study aimed to systematically investigate how end-tagging with hydrophobic residues at the C-terminus and Gly capped at the N-terminus of W4 (RWRWWWRWR) affects the bioactivity of W4 variants. Among all the hydrophobic residues, only Ala end-tagging improved the antibacterial activity of W4. Meanwhile, Gly capped at the N-terminus could promote the helical propensity of the end-tagged peptides in dodecylphosphocholine micelles, increasing their antimicrobial activities. Of these peptides, GW4A (GRWRWWWRWRA) showed the best antibacterial activity against the 19 species of bacteria tested (GM = 1.86 μM) with low toxicity, thus possessing the highest cell selectivity (TI = 137.63). It also had rapid sterilization, good salt and serum resistance, and LPS-neutralizing activity. Antibacterial mechanism studies showed that the short peptide GW4A killed bacteria by destroying cell membrane integrity and causing cytoplasmic leakage. Overall, these findings suggested that systematic studies on terminal modifications promoted the development of peptide design theory and provided a potential method for optimization of effective AMPs.