The present study details the development of a family of novel D-Ala8 glucagon-like peptide-1 (GLP-1) peptide conjugates by site specific conjugation to an antithrombin III (ATIII) binding carrier pentasaccharide through tetraethylene glycol linkers. All conjugates were found to possess potent insulin-releasing activity. Peptides with short linkers (<25 atoms) conjugated at Lys34 and Lys37 displayed strong GLP-1 receptor (GLP-1-R) binding affinity. All D-Ala8 GLP-1 conjugates exhibited prominent glucose-lowering action. Biological activity of the Lys37 short-linker peptide was evident up to 72 h post-injection. In agreement, the pharmacokinetic profile of this conjugate (t1/2, 11 h) was superior to that of the GLP-1-R agonist, exenatide. Once-daily injection of the Lys37 short-linker peptide in ob/ob mice for 21 days significantly decreased food intake and improved HbA1c and glucose tolerance.
- dipeptidyl peptidase IV
- glucagon-like peptide-1
- glucose homeostasis
Irwin, N., Patterson, S., de Kort, M., Moffett, R. C., Wisse, J. A. J., Dokter, W. H. A., Bos, E. S., Miltenburg, A. M. M., & Flatt, P. R. (2015). Synthesis and evaluation of a series of long-acting Glucagon-Like Peptide-1 (GLP-1) pentasaccharide conjugates for the treatment of type 2 diabetes. ChemMedChem, 10(8), 1424–1434 . https://doi.org/10.1002/cmdc.201500140