Position Effect of Fatty Acid Modification on the Cytotoxicity and Antimetastasis 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/ε-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 multifactors including
charge, size, helicity, hydrophobicity, and so forth. Of the eight
lipopeptides, L-C12 demonstrated highest cytotoxicity and
antimetastasis activity in two-dimensional cells, tumor spheroids,
subcutaneous transplantation mouse models, and experimental melanoma
metastasis mouse models. Collectively, our finding indicated that
fatty acid modification position plays important roles in physiochemical
parameters and biological activities of cytotoxic peptides.