Cagrilintide

Cagrilintide is a lipidated, long-acting analogue of the pancreatic hormone amylin, built on a 37-residue peptide chain. Native amylin readily forms amyloid fibrils, which makes it difficult to work with, and the structure-activity program behind cagrilintide focused on a stable, lipidated analogue with a prolonged half-life. The molecule has the formula C194H312N54O59S2 and a molar mass of about 4,409 g/mol. Pharmacologically it is classed as a non-selective agonist of the amylin receptors and the calcitonin receptor.

Cagrilintide in the research literature

Cryo-EM structures of cagrilintide bound to active, Gs-coupled amylin receptors AMY1R, AMY2R and AMY3R and to the calcitonin receptor (CTR) show an amylin-like binding mode, with distinct conformational dynamics at calcitonin-family receptors compared with rat amylin and salmon calcitonin. A second structural study described F23 anchoring the peptide at the transmembrane bundle, an E14 to R17 intramolecular salt bridge supporting helical stability, and C-terminal P37 contacts with the receptor extracellular domain, and reported non-selective Gs signaling through CTR and AMY1R.

In rodent models of energy balance, a cross-species single-cell transcriptomic atlas of the caudal brainstem identified calcitonin receptor-expressing neuron populations in the dorsal vagal complex that respond to cagrilintide, including upregulated prolactin-releasing hormone expression in nucleus of the solitary tract neurons in rats. In vitro metabolism studies have mapped N- and C-terminal degradation products that were also detected in rat plasma.