A novel thrombin-based triagonist with diabetes-protective and weight-lowering potential

Abstract

AimsTo investigate the diabetes-protective effect and weight-lowering potential of a novel long-acting triagonist at three metabolically related hormone receptors including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon receptors. Main methodsTriagonist were designed in an iterative manner from native GLP-1, GIP and Glucogan. Main peptide chain (termed TG peptides) and subsequently modified LTG peptides were synthesized via solid phase synthesis. In vitro receptor activity assay was performed to screen the TG peptide with most balanced potency on all three receptors. The in vitro biological activities of modified TG peptides were further investigated by albumin-binding measurement and proteolytic cleavage test. Subsequently, oral glucose tolerance test (OGTT), pharmacokinetic test and chronic study were subjected to the acute and long-term efficacy evaluation of selected fusion peptide, LTG-6. Key findingsTG-8 exhibited equally aligned constituent efficacy and supraphysiological potency on corresponding receptor without cross-reactivity. Modified TG-8, termed LTG-6, exerted the great binding affinity for human serum albumin and the enhanced rational controlled-release of TG-8 in vitro. Further OGTT in different gene knockout mice and diabetic mice demonstrated the promising hypoglycemic and insulinotropic abilities of LTG-6. After long-term treatment for 8 weeks, LTG-6 was proved superior to co-agonists to decrease the body weight and %HbA1c, improve reverse dyslipidemia and glycemic control in the DIO models. SignificanceLTG-6, as a newly designed long-acting triagonist, holds potential to correct the obesity related metabolic disorders.