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.