| Title | GZR18, a novel long-acting GLP-1 analog, demonstrated positive in vitro and in vivo pharmacokinetic and pharmacodynamic characteristics in animal models |
| Authors | Zhang, Man Zhang, Yining Peng, Xiaohong He, Anshun Wang, Yue Deng, Ying Cui, Cheng Xue, Fangkai Wei, Bing Xing, Wancai Qian, Yuzhen Mazuranic, Michelle Chen, Wei |
| Affiliation | Gan & Lee Pharmaceut, Beijing, Peoples R China Gan & Lee Pharmaceut USA Corp, Bridgewater, NJ USA Peking Univ, Inst Mol Med, State Key Lab Membrane Biol, Beijing Key Lab Cardiometab Mol Med, Beijing, Peoples R China |
| Keywords | GLUCAGON-LIKE PEPTIDE-1 AGONISTS |
| Issue Date | 5-Aug-2022 |
| Publisher | EUROPEAN JOURNAL OF PHARMACOLOGY |
| Abstract | GZR18 is a novel analog of glucagon-like peptide-1 (GLP-1). This study evaluates the pharmacology, pharmacokinetics, and efficacy of GZR18, and its potential for the treatment of Type 2 diabetes mellitus (T2DM). In vitro pharmacology and activity of GZR18 were characterized by a binding assay of GZR18 using human serum albumin (HSA), an activation assay in human GLP-1 receptor-expressing cell lines, and its effect on glucosestimulated insulin secretion (GSIS) in primary mice islets. Pharmacokinetic profiling was performed in Sprague Dawley rats and cynomolgus monkeys, and efficacy evaluated using GZR18 single or repeated doses in db/db mice. GZR18 showed similar binding affinity for HSA and GLP-1 receptor compared with semaglutide and liraglutide. GZR18 increased GSIS, which was confirmed by dynamic islet perifusion and fluorescence imaging using PKZnR-5 for real-time detection. In cynomolgus monkeys, the average GZR18 maximal concentration was 527 nmol L-1, the terminal half-life (T1/2) was 61.3 h, and the time to maximum concentration was 14 h. Singledose GZR18 lowered blood glucose levels and reduced body weight over 72 h in db/db mice. GZR18 successive administration (every three days for 33 days, i.e. 11 doses) lowered nonfasting and fasting blood glucose levels (p < 0.05 versus control) and glycated hemoglobin, following the 11th dose. Food and water consumption in db/ db mice was lowered following repeated doses of GZR18 (p < 0.05 versus control), without a reduction in body weight. These results demonstrate the potential of GZR18 as a long-acting GLP-1 analog for the treatment of T2DM. |
| URI | http://hdl.handle.net/20.500.11897/657456 |
| ISSN | 0014-2999 |
| DOI | 10.1016/j.ejphar.2022.175107 |
| Indexed | SCI(E) |
| Appears in Collections: | 分子医学研究所 膜生物学国家重点实验室 |
