Synthesis and evaluation of a series of long-acting Glucagon-Like Peptide-1 (GLP-1) pentasaccharide conjugates for the treatment of type 2 diabetes

Nigel Irwin*, Steven Patterson, Martin de Kort, R. Charlotte Moffett, Jeffry A.J. Wisse, Wim H.A. Dokter, Ebo S. Bos, Andre M.M. Miltenburg, Peter R. Flatt

*Corresponding author for this work

Research output: Contribution to journalArticle

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-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.
Original languageEnglish
Pages (from-to)1424–1434
Number of pages11
JournalChemMedChem
Volume10
Issue number8
Early online date9 Jun 2015
DOIs
Publication statusPublished - Aug 2015

Keywords

  • conjugates
  • dipeptidyl peptidase IV
  • glucagon-like peptide-1
  • glucose homeostasis
  • insulin
  • liraglutide

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    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