The Position Effect of Fatty Acid Modification on the Cytotoxicity and Anti-metastasis Potential of the Cytotoxic Peptide Lycosin-I

Peptide modification with fatty acids is an effective method to improve peptide performance. We previously investigated the fatty acid modification of R-lycosin-I, a cytotoxic peptide derived from Lycosin-I from the venom of the spider Lycosa singoriensis. In this study, we further investigated the position effects of fatty acid modification of Lycosin-I. Dodecanoic acid was covalently coupled to the α/e-amino group of one of the seven Lys residues of Lycosin-I, generating eight different lipopeptides. Although all the lipopeptides had significantly improved cytotoxicity compared with Lycosin-I, they displayed different cytotoxic potencies and profiles, which might be explained by multi-factors including charge, size, helicity and hydrophobicity etc. Of the eight lipopeptides, L-C12 demonstrated highest cytotoxicity and anti-metastasis activity in 2D cells, tumor spheroid, subcutaneous transplantation mouse model and experimental melanoma-metastasis mouse model. Collectively, our finding indicated that fa...