Peptide Half-Life Extension: Divalent, Small-Molecule Albumin Interactions Direct the Systemic Properties of Glucagon-Like Peptide 1 (GLP-1) Analogues
| Autor: | Knud J. Jensen, Søren Blok van Witteloostuijn, Søren L. Pedersen, Mikkel B. Thygesen, Manuel C. Martos-Maldonado, Jacob Jelsing, Niels Vrang, Kasper K. Sørensen, Pernille Wismann, Esben M. Bech |
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| Rok vydání: | 2017 |
| Předmět: |
Blood Glucose
0301 basic medicine endocrine system Indomethacin Diflunisal Peptide 01 natural sciences Glucagon-Like Peptide-1 Receptor Divalent Eating 03 medical and health sciences Glucagon-Like Peptide 1 Albumins Drug Discovery medicine Animals Hypoglycemic Agents Glucose homeostasis Receptor chemistry.chemical_classification 010405 organic chemistry digestive oral and skin physiology Albumin Human serum albumin Small molecule 0104 chemical sciences Mice Inbred C57BL 030104 developmental biology Biochemistry chemistry Drug Design Molecular Medicine hormones hormone substitutes and hormone antagonists Half-Life medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 60:7434-7446 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00787 |
| Popis: | Noncovalent binding of biopharmaceuticals to human serum albumin protects against enzymatic degradation and renal clearance. Herein, we investigated the effect of mono- or divalent small-molecule albumin binders for half-life extension of peptides. For proof-of-principle, the clinically relevant glucagon-like peptide 1 (GLP-1) was functionalized with diflunisal, indomethacin, or both. In vitro, all GLP-1 analogues had subnanomolar GLP-1 receptor potency. Surface plasmon resonance revealed that both small molecules were able to confer albumin affinity to GLP-1 and indicated that affinity is increased for divalent analogues. In lean mice, the divalent GLP-1 analogues were superior to monovalent analogues with respect to control of glucose homeostasis and suppression of food intake. Importantly, divalent GLP-1 analogues showed efficacy comparable to liraglutide, an antidiabetic GLP-1 analogue that carries a long-chain fatty acid. Finally, pharmacokinetic investigations of a divalent GLP-1 analogue demonstrated a promising gain in circulatory half-life and absorption time compared to its monovalent equivalent. |
| Databáze: | OpenAIRE |
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