Peptides – shipping from Europe

Research Disclaimer: This article is intended for educational and informational purposes regarding the chemical and biochemical properties of research compounds. All information is provided strictly in a scientific context. This content does not constitute medical advice, nor does it promote the use of any compound for human or veterinary application. All compounds referenced are for laboratory research use only.

Cagrilintide is a long-acting synthetic analogue of amylin (human islet amyloid polypeptide, IAPP) — a pancreatic peptide hormone with a distinct satiety mechanism from GLP-1. While less well known than GLP-1 receptor agonists, the amylin system represents a pharmacologically important and mechanistically distinct approach to appetite regulation. Understanding cagrilintide requires first understanding the native hormone it is derived from, the fundamental problem that native amylin presents, and how cagrilintide’s structure addresses that problem.

Native Amylin (IAPP): Biology and Limitations

Amylin — also called islet amyloid polypeptide (IAPP) — is a 37-amino acid peptide hormone co-secreted with insulin by pancreatic beta cells in response to food intake. It is the second major beta cell hormone and has several distinct metabolic effects:

The physiological effects of amylin complement those of insulin and GLP-1, but through partially non-overlapping neural circuits. This complementarity is the scientific rationale for combining amylin receptor agonism with GLP-1 receptor agonism.

The critical limitation of native amylin as a research or therapeutic compound is its extraordinary tendency to form amyloid aggregates. The hydrophobic core of IAPP (residues 20–29, particularly the sequence SNNFGAILSS) is one of the most amyloidogenic sequences known — it self-assembles into beta-sheet rich fibrils under physiological conditions. In patients with type 2 diabetes and in the beta cells of aged individuals, IAPP amyloid deposits are a histological hallmark. In experimental settings, native amylin solutions aggregate rapidly at the concentrations needed for pharmacological studies, making it impractical as a research tool.

Cagrilintide: Engineered to Solve the Aggregation Problem

Cagrilintide (INN designation; also referred to as AM833 or cagrilintide by Novo Nordisk) was developed to retain amylin’s receptor pharmacology while eliminating its amyloidogenic tendency and extending its half-life to enable once-weekly dosing.

Structural Modifications Compared to Native Amylin

Cagrilintide incorporates several types of modification relative to native human amylin, each targeting a specific property:

Anti-aggregation Substitutions

The amyloidogenic core of IAPP (residues 20–29) is modified by amino acid substitutions that disrupt the beta-sheet hydrogen bonding pattern without abolishing receptor binding. Specifically, substitutions in this region introduce residues with bulkier side chains or different hydrogen bonding properties that sterically prevent the intermolecular stacking needed for amyloid fibril formation. The specific substitutions in cagrilintide are part of Novo Nordisk’s proprietary design and are not fully disclosed, but the anti-aggregation principle is established in the broader amylin analogue literature.

Extended Half-Life: Fatty Acid Chain

Like semaglutide, cagrilintide incorporates a fatty acid modification that enables reversible binding to serum albumin. This dramatically extends the half-life from the minutes-to-hours range of native amylin to approximately one week — matching semaglutide’s dosing interval and enabling the once-weekly co-administration protocol studied in the CagriSema programme.

C-terminal Amide

Native amylin carries a C-terminal amide, which is required for receptor binding. Cagrilintide retains this structural feature. The C-terminal amide is added post-synthetically during solid-phase peptide synthesis using an amide resin.

Amylin Receptor Biology

The amylin receptor is not a simple single-chain GPCR like the GLP-1 receptor. It is an obligate heterodimer — a complex formed by two distinct proteins working together:

The RAMP protein determines which ligands the CTR can recognise with high affinity. Without a RAMP, CTR binds calcitonin well but has lower affinity for amylin. When CTR is complexed with RAMP1, 2, or 3, the combined receptor gains high affinity for amylin and related peptides while retaining calcitonin sensitivity. The molecular basis for this pharmacological transformation is the RAMP’s contribution to the peptide-binding extracellular domain — it physically alters the shape of the ligand-binding pocket.

This heterodimeric receptor architecture makes amylin receptor pharmacology distinctive and adds complexity to research design — the relative expression of RAMP1, RAMP2, and RAMP3 in different tissues determines which amylin receptor subtypes are present, which in turn influences the pharmacological response to cagrilintide.

Research History and the CagriSema Programme

The scientific case for combining amylin receptor agonism with GLP-1R agonism rests on the complementarity of their satiety mechanisms. GLP-1R activation primarily affects food motivation and meal frequency — the hedonic and homeostatic circuits that determine when and how often a person seeks food. Amylin receptor activation primarily affects meal size and eating rate — the signals that terminate an ongoing meal.

Rodent studies using selective receptor antagonists have shown that blocking GLP-1R does not abolish amylin’s satiety effects and vice versa, supporting the conclusion that the two systems operate through partially non-redundant neural circuits. This non-redundancy is what makes co-activation potentially additive rather than merely duplicative.

Cagrilintide entered clinical development at Novo Nordisk as a once-weekly amylin analogue. Phase 1 studies confirmed the pharmacokinetic profile and tolerability. Phase 2 studies of cagrilintide alone showed dose-dependent reductions in body weight. The CagriSema Phase 2 study — combining cagrilintide with semaglutide — published results in 2023 showing body weight reductions at the highest doses substantially greater than semaglutide alone at comparable doses, with findings broadly consistent with the additive satiety hypothesis.

ℹ️ Cagrilintide is not an approved pharmaceutical product. It is under clinical investigation. This article is for scientific research reference only. Research-grade cagrilintide is supplied for laboratory research use only.

Cagrilintide is available in research-grade, lyophilized form from the Aminopept research catalogue. Supplied for laboratory and in-vitro research use only.

→ View Cagrilintide in the research catalogue