Discovery of Insulin/GLP-1/Glucagon Triagonists for the Treatment of Diabetes and Obesity

Abstract

The combination of insulin and incretin-based therapies has emerged as a potential promising tactic for the treatment of diabetes. Here we report the first example of a unimolecular triagonist to simultaneously target insulin, GLP-1, and glucagon receptors, aiming for better glycemic control and superior weight loss. The strategy for constructing such a unimolecular triagonist is the conjugation of the insulin moiety and GLP-1R/GCGR coagonist peptide via alkyne–azide click chemistry. Two tractable series differentiated by insulin conjugation sites, B1F and B29K, were identified. Triagonist 13 prepared through the conjugation at insulin B1F and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity comparable to that of insulin degludec and potent and balanced GLP-1R and GCGR activities. Pharmacokinetic profiles of 13 in both rat and minipig were also discussed.

Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk

“…Conversely, whereas N-terminal B-chain residues are important for the foldability of proinsulin, they are dispensable for receptor binding; deletions or modifications are allowed among active analogs (42, 67, 68). Indeed, Huang et al recently described an insulin/glucagon/GLP-1 tri-agonist that uses “click” chemistry to bind the B-chain N-terminus of insulin to a C-terminal residue of a dual agonist (63). To our knowledge, the potential glucose responsiveness of this construct and its physical stability have not been evaluated.…”

“…The similar peptide sequences of GLP-1, glucagon, and to a lesser extent, glucose-dependent insulinotropic polypeptide (GIP)-and molecular homologies among their respective receptors-have enabled design of dual-and tripleagonists as exemplified by tirzepatide (Mounjaro ® ), a dual GLP-1/GIP agonist recently approved by the U.S. Food & Drug Administration for the treatment of T2D (60) and by the current development of Retatrutide, a GLP-1, GIP, and glucagon receptor agonist (61). Although not appropriate for management of T1D, these and related peptides are also under regulatory review for the treatment of obesity in the absence of diabetes (40,(62)(63)(64). Hypoglycemic risk is minimal except when used in combination with insulin or other insulin secretagogues (such as sulfonylureas).…”