Lipidation of Naturally Occurring α-Helical Antimicrobial Peptides as a Promising Strategy for Drug Design

In this paper, we describe the chemical synthesis, preliminary evaluation of antimicrobial properties and mechanisms of action of a novel group of lipidated derivatives of three naturally occurring α-helical antimicrobial peptides, LL-I (VNWKKVLGKIIKVAK-NH(2)), LK6 (IKKILSKILLKKL-NH(2)), ATRA-1 (KRFKKFFKKLK-NH(2)). The obtained results showed that biological properties of the final compounds were defined both by the length of the fatty acid and by the structural and physico-chemical properties of the initial peptide. We consider C(8)–C(12) length of the hydrocarbon chain as the optimal for antimicrobial activity improvement. However, the most active analogues exerted relatively high cytotoxicity toward keratinocytes, with the exception of the ATRA-1 derivatives, which had a higher selectivity for microbial cells. The ATRA-1 derivatives had relatively low cytotoxicity against healthy human keratinocytes but high cytotoxicity against human breast cancer cells. Taking into account that ATRA-1 analogues carry the highest positive net charge, it can be assumed that this feature contributes to cell selectivity. As expected, the studied lipopeptides showed a strong tendency to self-assembly into fibrils and/or elongated and spherical micelles, with the least cytotoxic ATRA-1 derivatives forming apparently smaller assemblies. The results of the study also confirmed that the bacterial cell membrane is the target for the studied compounds.