C-terminal site-specific PEGylated Exendin-4 analog: A long-acting glucagon like Peptide-1 receptor agonist, on glycemic control and beta cell function in diabetic db/db mice
| Autor: | Jicheng Wu, Xiangdong Gao, Cheng Luo, Jiaxiao Cheng, Wenbing Yao, Xiaoda Song, Hong Tian, Sai Wenbo, Daoqi Tang |
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| Rok vydání: | 2018 |
| Předmět: |
Blood Glucose
Male 0301 basic medicine Time Factors Dose Mice Inbred Strains Pharmacology Rats Sprague-Dawley Mice 03 medical and health sciences Pharmacokinetics Diabetes mellitus PEG ratio medicine Animals Hypoglycemic Agents Cells Cultured Glucagon-like peptide 1 receptor Dose-Response Relationship Drug Chemistry lcsh:RM1-950 medicine.disease Mice Inbred C57BL lcsh:Therapeutics. Pharmacology 030104 developmental biology Diabetes Mellitus Type 2 Delayed-Action Preparations Pharmacodynamics PEGylation Exenatide Molecular Medicine Hemoglobin Insulin Resistance |
| Zdroj: | Journal of Pharmacological Sciences, Vol 138, Iss 1, Pp 23-30 (2018) |
| ISSN: | 1347-8613 |
| Popis: | PEG modification is a common clinical strategy for prolonging the half-life of therapeutic proteins or polypeptides. In a previous work, we have successfully synthesized PEG-modified Exendin-4 (PE) by conjugating a 20 kDa PEG to the C-terminal of Exendin-4. Then, we introduced an integrative characterization for PE to evaluate its hypoglycemic activity and pharmacokinetic properties. The normoglycemic efficacies and therapeutic activity of PE were investigated in db/db mice. The hypoglycemic time after single administration of PE on db/db mice was prolonged from 8.4 h to 54.9 h. In multiple treatment with PE, the fasting blood glucose in various PE dosages (50, 150, and 250 nmol/kg) were remarkably reduced, and the glycosylated hemoglobin level was decreased to 2.0%. When the in vivo single- and multiple-dose pharmacokinetics of PE were examined in Sprague–Dawley rats, the half-life was prolonged to 31.7 h, and no accumulation effect was observed. Overall, this study provided a novel promising therapeutic approach to improving glucose-controlling ability and extending half-life without accumulation in vivo for long-acting treatment of type-2 diabetes. Keywords: GLP-1 mimetic, PEGylation, db/db mice, Pharmacodynamics, Pharmacokinetics |
| Databáze: | OpenAIRE |
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