Cagrilintide is a long-acting, acylated analog of amylin, the peptide hormone released from pancreatic β-cells together with insulin. It was designed by Novo Nordisk to overcome two problems that make native human amylin hard to study: a strong tendency to clump into amyloid fibrils and a half-life of only minutes in circulation.
The peptide activates both amylin receptors and the calcitonin receptor, which places it in the group of non-selective amylin analogs. That profile, along with its stability, has made it a reference compound for research on hindbrain satiety circuits and on how amylin and incretin pathways interact. This overview covers amylin biology, how cagrilintide was engineered, its receptor pharmacology and the limits of the published data.
At a glance
- Class: Synthetic acylated amylin analog peptide; non-selective amylin and calcitonin receptor agonist
- Origin: Novo Nordisk; development described by Kruse and colleagues in 2021
- Structure: Amylin-based peptide with stabilizing substitutions and a fatty-acid side chain; C194H312N54O59S2; MW 4409.0 g/mol; CAS 1415456-99-3
- Main research areas: AMY and calcitonin receptor pharmacology, peptide fibrillation and stability, area postrema signaling in rodents, amylin–GLP-1 pathway interactions
- Regulatory status: Investigational; not approved by the FDA as a standalone drug; research reagent only
Structure and origin
Amylin, also called islet amyloid polypeptide, was identified in 1987 as the main protein in the amyloid deposits found in the pancreas in type 2 diabetes. It is a 37-residue peptide with a disulfide bridge near the N-terminus and an amidated C-terminus, related to calcitonin and calcitonin gene-related peptide (CGRP). Its aggregation-prone middle segment makes the native human peptide difficult to formulate. An earlier analog, pramlintide, replaced three residues with proline, as found in non-aggregating rat amylin, and was approved by the FDA in 2005 (Hay et al., 2015).
Kruse and colleagues took a different route to a long-acting molecule. Starting from amylin, they introduced substitutions to reduce fibrillation and improve solubility and chemical stability, then attached a fatty diacid side chain through a linker. The lipid chain binds serum albumin reversibly, which slows clearance and gives a much longer half-life than native amylin. The program screened variants for receptor potency, physical stability and duration of action before settling on cagrilintide (Kruse et al., 2021).
Mechanism: what the research shows
Amylin signals through a two-part receptor. The calcitonin receptor (CTR), a class B G protein-coupled receptor, can partner with one of three receptor activity-modifying proteins (RAMP1, 2 or 3). The resulting complexes, AMY1, AMY2 and AMY3, respond to amylin with high potency, whereas CTR alone prefers calcitonin. Signaling runs mainly through Gs and cAMP, with additional pathways reported (Hay et al., 2018).
In cell lines expressing CTR alone or CTR with defined RAMPs, cagrilintide activated both amylin receptors and the calcitonin receptor with high potency (Kruse et al., 2021). In rodents, amylin receptors are concentrated in the area postrema and nucleus of the solitary tract of the hindbrain, regions that relay satiety and gastric-emptying signals to the hypothalamus and reward circuits (Boyle et al., 2018).
Key areas of study
Receptor pharmacology
cAMP accumulation assays and radioligand binding in HEK293 or COS-7 cells transfected with CTR and individual RAMPs are the standard way to profile amylin analogs. These systems let researchers compare potency at AMY1, AMY2, AMY3 and CTR and classify compounds as selective or non-selective (Hay et al., 2018).
Peptide engineering and stability
Thioflavin T fibrillation assays, solubility measurements across pH and plasma stability studies were central to cagrilintide’s design. The compound is a worked example of how acylation and sequence changes can be combined to make an aggregation-prone hormone usable as a research tool (Kruse et al., 2021).
Hindbrain satiety circuits
In rats and mice, amylin and its analogs activate neurons in the area postrema, and lesion and receptor-knockdown studies show that this region is needed for many of amylin’s effects on food intake in the model. Long-acting analogs such as cagrilintide allow these circuits to be studied over longer periods (Boyle et al., 2018).
Combination pharmacology
Preclinical studies have paired amylin-receptor agonists with GLP-1 receptor agonists to ask whether the two pathways act through overlapping or distinct brain regions. Amylin acts mainly at the area postrema, while GLP-1 signaling involves additional hindbrain and hypothalamic sites (Boyle et al., 2018).
What the evidence does not show
Because cagrilintide activates CTR as well as AMY receptors, it is hard to say which of its effects come from amylin-receptor signaling specifically; newer selective analogs were designed partly to answer that question. Most detailed pharmacology comes from the developer’s own studies. Rodent amylin receptor distribution and RAMP expression do not map perfectly onto other species. Cagrilintide has been evaluated in clinical studies, but this article makes no claim about human outcomes, and preclinical findings do not establish effects in people.
Regulatory status
Cagrilintide is an investigational compound developed by Novo Nordisk. It has been evaluated in clinical studies, alone and in combination with a GLP-1 receptor agonist, and it is not approved by the FDA as a standalone drug. The cagrilintide sold by Rogue Compounds is a research reagent only.
Handling and storage in the lab
Lyophilized cagrilintide should be kept sealed and refrigerated at 2–8°C (36–46°F), protected from light. Keep the vial closed until use to protect the peptide from moisture.
Sourcing and documentation
Rogue Compounds has cagrilintide made in small batches. Every vial carries a batch number and a QR code that opens the independent U.S. testing lab’s own report for that batch. The same batch COA is posted on the product page and in the COA Library.
View Cagrilintide on Rogue Compounds
References
- Kruse T, et al. Development of cagrilintide, a long-acting amylin analogue. J Med Chem. 2021;64(15):11183-11194. PMID 34288673
- Hay DL, et al. Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev. 2015;67(3):564-600. PMID 26071095
- Hay DL, et al. Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol. 2018;175(1):3-17. PMID 29059473
- Boyle CN, Lutz TA, Le Foll C. Amylin – its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Mol Metab. 2018;8:203-210. PMID 29203236
Research use only. Rogue Compounds products are sold strictly for laboratory research. They are not for human or veterinary use, and nothing in this article is medical advice. The studies cited here describe published research, not this product or any use of it.