Research overview

Cagrilintide is a novel long-acting acylated amylin analogue that functions as a dual agonist of non-selective amylin receptor (AMYR) and calcitonin gene-related peptide receptor (CTR). Natural amylin is a neuroendocrine hormone secreted by pancreatic β cells, playing a crucial role in glucose homeostasis and energy balance regulation. Its physiological effects include delaying gastric emptying, inhibiting post-meal glucagon secretion, and promoting satiety. Cagrilintide overcomes the pharmacokinetic limitation of the extremely short half-life of natural amylin through acylation modification. The mechanism of action of Cagrilintide involves multiple aspects: It exerts its effect by binding and activating the pancreatic amylin and calcitonin receptors in key areas of the brain involved in appetite control (such as the posterior region and the hypothalamus). Structural studies have shown that Cagrilintide adopts a similar "side-channel" binding pattern in AMY1R and CTR. Its key molecular features include the anchoring of the F23 residue to the transmembrane bundle of the receptor, the intramolecular salt bridge at E14-R17 enhancing the stability of the helix, and the interaction of the C-terminal P37 with the ECD of the receptor. Cryo-electron microscopy structure analysis further revealed the detailed structure of Cagrilintide binding to Gs-coupled active AMY1R, AMY2R, AMY3R, and CTR.