Monosaccharide Analogues of Anticancer Peptide R‑Lycosin-I: Role of Monosaccharide Conjugation in Complexation and the Potential of Lung Cancer Targeting and Therapy

Glycoconjugation is a promising modification strategy for the optimization of peptide drugs. In this study, five different monosaccharide derivatives (7a–e) were covalently linked to the N-terminal of R-lycosin-I, which yielded five glycopeptides (8a–e). They demonstrated increased or reduced cytotoxicity depending on monosaccharide types, which might be explained by the changes of physicochemical properties. Among all synthesized glycopeptides, only 8a exhibited increased cytotoxicity (IC50 = 9.6 ± 0.3 μM) and selectivity (IC50 = 37.4 ± 5.9 μM). The glucose transporter 1 (GLUT1) with high expression in cancer cells was approved to be involved in the cytotoxicity and selectivity enhancement of 8a. Furthermore, 8a but not R-lycosin-I inhibited tumor growth in the nude mice xenograft model without generating side effects intraperitoneally. Taken together, this study reveals the different monosaccharide roles in peptide modification and also provides an optimized anticancer peptide with high activity and selectivity, that is, 8a might be a promising lead for developing anticancer drugs.