Design of a Long Acting Peptide Functioning as Both a Glucagon-like Peptide-1 Receptor Agonist and a Glucagon Receptor Antagonist
| Autor: | Andrea Bell, Stephanie L. Yung, Ling Yang, Joanne M. Buxton, Clark Q. Pan, Thomas H. Claus, Hongxing Chen, James Whelan, Kevin B. Clairmont, Margit MacDougall, Irene Tom |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Blood Glucose
Male Agonist endocrine system medicine.medical_specialty medicine.drug_class Molecular Sequence Data Peptide Biology Biochemistry Glucagon Glucagon-Like Peptide-1 Receptor Rats Sprague-Dawley Internal medicine Receptors Glucagon medicine Animals Humans Inverse agonist Amino Acid Sequence Rats Wistar Molecular Biology Peptide sequence Glucagon-like peptide 1 receptor chemistry.chemical_classification Sequence Homology Amino Acid digestive oral and skin physiology Cell Biology Rats Endocrinology Diabetes Mellitus Type 2 chemistry Drug Design Peptides Glucagon receptor Glucagon receptor family hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Biological Chemistry. 281:12506-12515 |
| ISSN: | 0021-9258 |
| Popis: | The closely related peptides glucagon-like peptide (GLP-1) and glucagon have opposing effects on blood glucose. GLP-1 induces glucose-dependent insulin secretion in the pancreas, whereas glucagon stimulates gluconeogenesis and glycogenolysis in the liver. The identification of a hybrid peptide acting as both a GLP-1 agonist and a glucagon antagonist would provide a novel approach for the treatment of type 2 diabetes. Toward this end a series of hybrid peptides made up of glucagon and either GLP-1 or exendin-4, a GLP-1 agonist, was engineered. Several peptides that bind to both the GLP-1 and glucagon receptors were identified. The presence of glucagon sequence at the N terminus removed the dipeptidylpeptidase IV cleavage site and increased plasma stability compared with GLP-1. Targeted mutations were incorporated into the optimal dual-receptor binding peptide to identify a peptide with the highly novel property of functioning as both a GLP-1 receptor agonist and a glucagon receptor antagonist. To overcome the short half-life of this mutant peptide in vivo, while retaining dual GLP-1 agonist and glucagon antagonist activities, site-specific attachment of long chained polyethylene glycol (PEGylation) was pursued. PEGylation at the C terminus retained the in vitro activities of the peptide while dramatically prolonging the duration of action in vivo. Thus, we have generated a novel dual-acting peptide with potential for development as a therapeutic for type 2 diabetes. |
| Databáze: | OpenAIRE |
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