The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Hunan Normal University), Ministry of Education, College of Chemistry & Chemical Engineering, Changsha, Hunan 410081, China.
J Med Chem. 2021 Aug 12;64(15):11483-11495. doi: 10.1021/acs.jmedchem.1c00805. Epub 2021 Jul 20.
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-C, 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-C-4 exhibited the highest cytotoxicity and improved selectivity. A further study demonstrated that R-C-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-C-4 might be a promising lead for developing anticancer drugs.
糖基化和脂肪酸修饰是改善肽性能的有前途的策略。我们之前研究了抗癌肽 R-糖蛋白-I 的糖基化和脂肪酸修饰。在这项研究中，我们进一步研究了 R-糖蛋白-I 中脂肪酸和单糖的共修饰。将葡萄糖衍生物通过共价键连接到源自用十二烷酸修饰的 R-糖蛋白-I 的脂肽 R-C 的 Lys 残基的 ε-氨基上，得到了七种糖脂肽。它们表现出不同的细胞毒性谱，这可能与理化性质和与葡萄糖转运蛋白 1 (GLUT1) 的结合能力的变化有关。其中，R-C-4 表现出最高的细胞毒性和提高的选择性。进一步的研究表明，R-C-4 在小鼠黑色素瘤细胞、黑色素瘤球体和动物模型中表现出显著的细胞毒性和抗转移活性。我们的结果表明，葡萄糖衍生物修饰位置在葡萄糖脂肽缀合物中起着重要作用，R-C-4 可能是开发抗癌药物的有前途的先导化合物。
