Premium
Synthesis and Evaluation of a Series of Long‐Acting Glucagon‐Like Peptide‐1 (GLP‐1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes
Author(s) -
Irwin Nigel,
Patterson Steven,
de Kort Martin,
Moffett R. Charlotte,
Wisse Jeffry A. J.,
Dokter Wim H. A.,
Bos Ebo S.,
Miltenburg André M. M.,
Flatt Peter R.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500140
Subject(s) - exenatide , chemistry , peptide , conjugate , linker , agonist , glucagon like peptide 1 , glucagon like peptide 1 receptor , islet , receptor , liraglutide , conjugated system , insulin , pharmacology , biochemistry , stereochemistry , medicine , endocrinology , type 2 diabetes , diabetes mellitus , mathematical analysis , operating system , polymer , organic chemistry , mathematics , computer science
The present study details the development of a family of novel D ‐Ala 8 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 Lys 34 and Lys 37 displayed strong GLP‐1 receptor (GLP‐1‐R) binding affinity. All D ‐Ala 8 GLP‐1 conjugates exhibited prominent glucose‐lowering action. Biological activity of the Lys 37 short‐linker peptide was evident up to 72 h post‐injection. In agreement, the pharmacokinetic profile of this conjugate ( t 1/2 , 11 h) was superior to that of the GLP‐1‐R agonist, exenatide. Once‐daily injection of the Lys 37 short‐linker peptide in ob / ob mice for 21 days significantly decreased food intake and improved HbA 1c and glucose tolerance. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys 37 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.