Small-molecule albumin ligand modification to enhance the anti-diabetic ability of GLP-1 derivatives.

Glucagon-like peptide-1 (GLP-1) receptor agonists modified with albumin ligands which can specificity bind to the human serum albumin (HSA) was an efficient strategy to prolong the half-time of GLP-1. Herein, we investigated the effect of small-molecule albumin ligand modification on the hypoglycemic activities of GLP-1 derivatives. Two GLP-1 derivatives MPA-C12-GLP-1 and Rhein-C12-GLP-1 were achieved by modification of the side chain amino of lysine in position 26 of the Arg34-GLP-1(7-37)-OH with Rhein and 3-Maleimidopropionic acid respectively using 12-aminolauric acid as a linker, and its specific albumin-conjugating characteristics, pharmaceutical characterization, and the antidiabetic effects were investigated. In vitro level, two GLP-1 derivatives demonstrated a higher binding capacity to GLP-1 receptor than that of Arg34-GLP-1(7-37)-OH. Interestingly, although the binding ability of MPA-C12-GLP-1 was equal to liraglutide, the binding ability of Rhein-C12-GLP-1 was 10-fold higher than liraglutide. In vivo level, the two GLP-1 derivatives can significantly increase their glucose tolerance and prolong their half-life in ICR mice, and they were also superior to GLP-1 in controlling glucose homeostasis and suppression of food intake and water consumption in db/db mice. Importantly, the two GLP-1 derivatives showed comparable efficacy to liraglutide for the therapy of type 2 diabetes mellitus. The in vitro INS-1 cells toxicity and the in vivo hepatotoxicity indicated that the Rhein-C12-GLP-1 was a safe candidate for the therapy of type 2 diabetes, and the serum biomarkers determination results showed that the Rhein-modified GLP-1 could significantly improve the HbA1c and blood lipids, and the H&E stain exhibited that the Rhein-C12-GLP-1 can effectively promote ß-cell proliferation and differentiation. In conclusion, the 3-Maleimidopropionic acid or Rhein-modified GLP-1derivatives have great potential for development as a Type 2 diabetes mellitus therapeutic drug.

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.

Position Effect of Fatty Acid Modification on the Cytotoxicity and Antimetastasis Potential of the Cytotoxic Peptide Lycosin-I.

Peptide modification with fatty acids is an effective method to improve peptide performance. We previously investigated the fatty acid modification of R-lycosin-I, a cytotoxic peptide derived from lycosin-I from the venom of the spider Lycosa singoriensis. In this study, we further investigated the position effects of fatty acid modification of lycosin-I. Dodecanoic acid was covalently coupled to the α/ε-amino group of one of the seven Lys residues of lycosin-I, generating eight different lipopeptides. Although all the lipopeptides had significantly improved cytotoxicity compared with lycosin-I, they displayed different cytotoxic potencies and profiles, which might be explained by multifactors including charge, size, helicity, hydrophobicity, and so forth. Of the eight lipopeptides, L-C12 demonstrated highest cytotoxicity and antimetastasis activity in two-dimensional cells, tumor spheroids, subcutaneous transplantation mouse models, and experimental melanoma metastasis mouse models. Collectively, our finding indicated that fatty acid modification position plays important roles in physiochemical parameters and biological activities of cytotoxic peptides.