ZY-GLP1: A Novel Peptidomimetic Glp-1 Agonist

摘要

Type-2 diabetes mellitus (T2DM) is characterized by increased blood glucose levels, either because of defect in insulin secretion or due to insulin resistance or a combination of both [1], During the last decade, incretin hormones such as Glucagon-Like Peptide (GLP-1) have been extensively explored in order to develop new therapeutic agents for the safe and effective treatment of T2DM [2]. GLP-1 stimulates insulin secretion from the pancreatic β-cells in a glucose-dependent manner, prevents pre- and post-prandial hyperglycemia, suppresses glucagon secretion from pancreatic α-cells, delays gastric emptying, reduces food intake and stimulates β-cell proliferation [3]. The native GLP-1 has an extremely short half-life as it is rapidly degraded by the enzyme DPP-IV. Although continuous infusions of GLP-1 could be useful for the short-term control of hyperglycemia, the long-term treatment of T2DM would require a more feasible approach to achieve sustained activation of GLP-1 receptors. Exendin-4 was discovered as the first clinically relevant, potent and metabolically stable GLP-1 receptor (GLP-1 R) agonist. Exendin-4 at 10 ug (sc twice a day) dose effectively reduces elevated plasma glucose level and HbAlc levels [4]. Under clinical regime, Exendin-4 treatment causes incidences of nausea and vomiting, immunogenicity, pancreatitis, hypoglycemia (in combination therapy) and reaction at the site of injection [5]. Thus Exendin-4 represents a potent GLP-1 agonist with several safety concerns. Considering these side-effects of Exendin-4, we decided to develop ZY-GLP1, a short-chain peptidomimetic based novel GLP-1 agonists, for long-term treatment of T2DM.