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, Rachel C Moffett, Jeffry Wisse, Wim Dokter, Ebo Bos, Andre Miltenburg, Peter Flatt

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

Fingerprint

Glucagon-Like Peptide 1
Medical problems
Type 2 Diabetes Mellitus
Peptides
Glucose
Injections
Glycols
Pharmacokinetics
Antithrombin III
Therapeutics
Bioactivity
Eating
Insulin
Atoms

Keywords

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

Cite this

Irwin, Nigel ; Patterson, Steven ; de Kort, Martin ; Moffett, Rachel C ; Wisse, Jeffry ; Dokter, Wim ; Bos, Ebo ; Miltenburg, Andre ; Flatt, Peter . / Synthesis and evaluation of a series of long-acting Glucagon-Like Peptide-1 (GLP-1) pentasaccharide conjugates for the treatment of type 2 diabetes. In: ChemMedChem. 2015 ; Vol. 10, No. 8. pp. 1424–1434 .
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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.",
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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, Steven; de Kort, Martin; Moffett, Rachel C; Wisse, Jeffry; Dokter, Wim; Bos, Ebo ; Miltenburg, Andre; Flatt, Peter .

In: ChemMedChem, Vol. 10, No. 8, 08.2015, p. 1424–1434 .

Research output: Contribution to journalArticle

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AU - Irwin, Nigel

AU - Patterson, Steven

AU - de Kort, Martin

AU - Moffett, Rachel C

AU - Wisse, Jeffry

AU - Dokter, Wim

AU - Bos, Ebo

AU - Miltenburg, Andre

AU - Flatt, Peter

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AB - 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.

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