Cagrilintide

A long-acting analogue of the pancreatic peptide hormone amylin carrying a fatty diacid lipidation on the chain. Lipidated analogues sit outside the PepXtide structural library, which models plain peptide chains.

The parent hormone, amylin, is a 37-residue peptide with a C-terminal tyrosine amide and a disulfide between cysteines two and seven, and it is strongly amyloidogenic. This analogue is also 37 residues, retains that native disulfide, and ends in a proline amide rather than a tyrosine amide. It is not a lactam-bridged peptide, and the frequently repeated description of it as a 32-residue compound is wrong.

Six substitutions separate it from human amylin, and the reasons are documented in the originating work published by Novo Nordisk in 2021. A glutamate at position 14 and an arginine at position 17 form an intramolecular salt bridge that stabilises the N-terminal helix, specifically to counteract the fibril formation the native hormone undergoes. Three prolines, at positions 25, 28 and 29, reduce the tendency to fibrillise further, and the proline that replaces the C-terminal tyrosine at position 37 was selected for solubility and physical stability. The crystal structure of the backbone has been deposited in the Protein Data Bank.

The lipidation is unusual and worth stating precisely, because it differs from the pattern used by the incretin analogues in this catalogue. A C20 eicosanedioic diacid is attached through a single gamma-glutamate spacer to the alpha-amino nitrogen of the N-terminal lysine. There is no oligoethylene-glycol spacer, and the lysine's side-chain epsilon-amine remains free. The diacid is the albumin-binding element that gives the analogue its duration.

The molecular targets are the calcitonin receptor on its own and the same receptor in complex with receptor activity-modifying proteins RAMP1, RAMP2 and RAMP3, which constitute the three amylin receptor subtypes. The compound is described as a non-selective agonist across the amylin receptors and the calcitonin receptor, in contrast to the earlier analogue pramlintide, which is amylin-receptor selective. Reported potencies at the calcitonin receptor and at amylin receptor 3 are in the sub-nanomolar range, though published datasets differ on whether particular figures describe the human or the rat receptors, so a single quoted number should always name its assay system and species.

Bench systems for this class are receptor-expression rather than tissue systems: reporter assays in BHK cells stably expressing the human calcitonin receptor with or without RAMP3, G-protein recruitment measured by bioluminescence resonance energy transfer in COS-7 cells, and radioligand displacement using iodinated amylin or calcitonin. Fibril formation is assessed by thioflavin T fluorescence and solubility across pH by UPLC. Several cryo-electron microscopy structures of the compound bound to amylin receptor complexes have been published.

One specification note. The published molecular weight near 4409 is the full modified mass including the lipid; no backbone-only figure is published for this compound, and a lower number quoted without qualification is likely to be an unlipidated calculation rather than the substance itself.