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

ID: ALA5036332

Journal: J Med Chem

Title: Glucose-Lipopeptide Conjugates Reveal the Role of Glucose Modification Position in Complexation and the Potential of Malignant Melanoma Therapy.

Authors: Zhao X, Zhang P, Li Y, Wu S, Li F, Wang Y, Liang S, He X, Zeng Y, Liu Z.

Abstract: 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.

CiteXplore: 34282902

DOI: 10.1021/acs.jmedchem.1c00805

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