Abstract
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‐Ala8GLP‐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. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys37 short‐linker peptide were similar to or better than either exenatide or liraglutide, another GLP‐1‐R agonist. In conclusion, GLP‐1 peptides conjugated to an ATIII binding carrier pentasaccharide have a substantially prolonged bioactive profile compatible for possible once‐weekly treatment of type 2 diabetes in humans.
Original language | English |
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Pages (from-to) | 1424-1434 |
Number of pages | 11 |
Journal | ChemMedChem |
Volume | 10 |
Issue number | 8 |
Early online date | 9 Jun 2015 |
DOIs | |
Publication status | Published (in print/issue) - 23 Jul 2015 |
Keywords
- conjugates
- dipeptidyl peptidase IV
- glucagon-like peptide-1
- glucose homeostasis
- insulin
- liraglutide
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Charlotte Moffett
- School of Biomedical Sciences - Lecturer in Pharmacology and Molecular Pathology
- Faculty Of Life & Health Sciences - Lecturer
Person: Academic