N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity
| Autor: | Mark Mooney, Victor A. Gault, Brian D. Green, P Harriott, C. J. Bailey, Nigel Irwin, Peter R. Flatt, Finbarr O'Harte, B Greer |
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| Rok vydání: | 2004 |
| Předmět: |
endocrine system
medicine.medical_specialty Dipeptidyl Peptidase 4 Endocrinology Diabetes and Metabolism medicine.medical_treatment Glucagon-Like Peptides Mice Obese Peptide Glucagon Dipeptidyl peptidase Mice Endocrinology Glucagon-Like Peptide 1 In vivo Cricetinae Internal medicine Cyclic AMP Diabetes Mellitus medicine Animals Hypoglycemic Agents Insulin Protein Precursors Dipeptidyl peptidase-4 Cell Line Transformed chemistry.chemical_classification Mesocricetus digestive oral and skin physiology Biological activity Glucagon-like peptide-1 Peptide Fragments Pyrrolidonecarboxylic Acid chemistry hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Endocrinology. 180:379-388 |
| ISSN: | 1479-6805 0022-0795 |
| Popis: | Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P |
| Databáze: | OpenAIRE |
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