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Synthesis and Evaluation of a Series of Long-Acting Glucagon-Like Peptide-1 (GLP-1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes.

Irwin, Nigel, Patterson, S, de Kort, M, Moffett, Charlotte, Wisse, JA, Dokter, WH, Bos, ES, Miltenburg, AM and Flatt, Peter (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.. [Journal article]

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DOI: 10.1002/cmdc.201500140

Abstract

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 (t1/2 , 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 HbA1c 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

Item Type:Journal article
Keywords:conjugates; dipeptidyl peptidase IV; glucagon-like peptide-1; glucose homeostasis; insulin; liraglutide
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:32289
Deposited By: Dr Nigel Irwin
Deposited On:22 Sep 2015 08:11
Last Modified:09 May 2016 11:23

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