Glucose–Lipopeptide Conjugates Reveal the Role of Glucose Modification Position in Complexation and the Potential of Malignant Melanoma Therapy

Glycosylation and fatty acid modification are promising strategies to improve peptide performance. We previously studied glycosylation and fatty acid modification of the anticancer peptide R-lycosin-I. In this study, we further investigated the co-modification of fatty acids and monosaccharides in R-lycosin-I. A glucose derivative was covalently coupled to the ε-amino group of the Lys residues of the lipopeptide R-C12, which was derived from R-lycosin-I modified with dodecanoic acid, and obtained seven glycolipid peptides. They exhibited different cytotoxicity profiles, which may be related to the changes in physicochemical properties and binding ability to glucose transporter 1 (GLUT1). Among them, R-C12-4 exhibited the highest cytotoxicity and improved selectivity. A further study demonstrated that R-C12-4 showed significant cytotoxicity and antimetastasis activity in murine melanoma cells, melanoma spheroids, and animal models. Our results indicated that the glucose derivative modification position plays important roles in glucose–lipopeptide conjugates, and R-C12-4 might be a promising lead for developing anticancer drugs.