Description
PrymaLab · Research Use Only
Cagrilintide 10mg
Engineered against the one thing its parent molecule is famous for
Most analogues in this catalogue were built to last longer in circulation. Cagrilintide peptide was built for that too, but the harder problem its designers faced was different. The natural hormone it derives from aggregates into amyloid fibrils, reliably and well, and an analogue that did the same would be unusable.
Specification Table
| Property | Value |
|---|---|
| Compound | Cagrilintide |
| Development codes | AM833 and NNC0174-0833 |
| CAS number | 1415456-99-3 |
| Class | Long-acting amylin analogue, lipidated and disulfide bridged |
| Molecular formula | C194H312N54O59S2 |
| Molecular weight | Approximately 4409 for the free peptide. A salt form adds counterion mass |
| Parent hormone | Human amylin, also called islet amyloid polypeptide, 37 residues |
| Structural inheritance | A disulfide bridge and a C-terminal amide, both retained from the parent |
| Modification | A fatty acid chain attached through a linker, the same approach used on other long-acting analogues |
| Reported targets | The amylin receptor and the calcitonin receptor |
| Reported binding, human AMY3R | IC50 in the region of 170 pM |
| Reported binding, human CTR | IC50 in the region of 223 pM |
| Reported aggregation behaviour | A thioflavin T lag time near 45 hours at 250 µM in the development paper |
| Regulatory status | Investigational. No approval as a single agent |
| Vial | 10mg lyophilized |
| Storage | Sealed at minus 20°C. Do not freeze reconstituted solution and do not agitate |
Why Does Human Amylin Aggregate?
Amylin, also called islet amyloid polypeptide, is a 37 residue hormone co-secreted with insulin from pancreatic beta cells.
It is also one of the most thoroughly characterised amyloid forming peptides in biology, and the deposits it forms in the islets are a defining pathological feature of type 2 diabetes in humans.
The behaviour is sequence specific rather than general. A stretch in the middle of the human sequence adopts a beta strand conformation readily, and once a few molecules have done so together they present a template that recruits more.
Rodent amylin differs across that region by a handful of proline substitutions and does not aggregate the same way, which is why rodent models understate the problem and why the comparison appears in almost every review of the field.
Westermark and colleagues set out the structural and pathological picture in detail, and the short version is that the aggregation is not an artefact of handling. It is what the molecule does.
This creates a straightforward problem for anyone wanting to use amylin pharmacology as a tool.
A peptide that converts to fibrils in solution changes concentration over the course of an experiment, and the species present at the end is not the species that was added at the start.
Cagrilintide peptide, like every analogue in this class, had to solve stability before it could be useful for anything else.
What Did the Design Change?
Kruse and colleagues published the cagrilintide peptide development work in 2021, and the paper is unusually readable about the trade-offs involved.
Two things were done at once, and they pull in different directions.
The first was to attach a fatty acid chain through a linker, the same acylation approach used to extend circulation time on other long-acting analogues. Acylation works by promoting reversible binding to serum albumin, which slows clearance.
The second was to substitute residues in the aggregation prone region so that the beta strand conformation becomes less accessible.
The tension is that a fatty acid chain is a strongly self-associating feature. Adding one to a peptide that already aggregates could easily have made the situation worse rather than better.
Resolving that is most of what the development paper describes, and the reported outcome is a molecule that carries the lipid chain and still resists fibril formation for a long time under conditions that convert the parent quickly.
The figure reported in that work is a thioflavin T lag time near 45 hours at 250 micromolar, which is a long lag for a peptide of this class at that concentration.
The cagrilintide peptide disulfide bridge and its C-terminal amide are both retained from the parent hormone, so the analogue is a modified version of the natural sequence rather than a redesign of it.
What Is a Thioflavin T Lag Time?
Thioflavin T is a small fluorescent dye whose emission increases sharply when it binds to the beta sheet structure characteristic of amyloid fibrils.
In a fibrillation assay the dye is incubated with the peptide and fluorescence is followed over time.
The curve that comes out has a characteristic shape: a flat stretch where little is happening, then a steep rise, then a plateau once the available material has converted.
The flat stretch is the lag time, and it is the number worth reading.
What happens during the lag is nucleation, the slow and stochastic formation of the first ordered aggregates. Once those exist, growth is fast, because a fibril end is an efficient template.
That is why lag time rather than final fluorescence is the useful metric. A long lag says the molecule struggles to start, which is the property a researcher actually needs.
It also explains an experimental behaviour that catches people out. Nucleation is stochastic, so replicate wells of the same preparation can begin converting at noticeably different times, and a single well tells you less than it appears to.
Seeding is the other consequence. Introducing a small quantity of preformed fibril removes the nucleation step entirely and collapses the lag, which is why contaminated glassware or a previously aggregated stock can undermine an otherwise clean preparation.
Why Does Aggregation Matter at the Bench?
The practical answer is that aggregation is invisible to the measurement most laboratories rely on.
A solution prepared from a weighed vial has a nominal concentration derived from mass and volume. If a fraction of the peptide has converted to fibrils, the mass is unchanged and the nominal concentration is unchanged.
What has changed is the amount of monomeric peptide available to engage a receptor, and that is the quantity the experiment is actually sensitive to.
The consequence is a systematic underestimate of potency that looks like ordinary variability.
Two laboratories following the same written method can report different figures, neither has made a detectable error, and the difference sits in how long each stock sat and how it was handled.
Size exclusion chromatography detects the problem directly by separating aggregate from monomer, and it is the single most useful check to run on a stock that has been held for any length of time.
A dynamic light scattering measurement is faster and catches gross aggregation, though it is less informative about the distribution.
Visual inspection catches only the end state. By the time a solution looks hazy the useful material is largely gone.
None of this is exotic instrumentation and none of it is routine either, which is the gap worth closing on a compound whose parent molecule is a textbook amyloid former.
What Does Dual Receptor Engagement Mean?
Cagrilintide peptide is reported to engage both the amylin receptor and the calcitonin receptor, with binding figures in the same range at each.
That is not an accident of promiscuity. The amylin receptors are themselves built from the calcitonin receptor, which associates with accessory proteins to change its ligand preference, so the two targets are structurally related at a deep level.
A compound with comparable affinity at both cannot be used to attribute an effect to one of them.
The design consequence is the same as for any non-selective tool. Attribution requires a system where one receptor is absent or blocked, run alongside the compound rather than instead of it.
The published binding figures sit in the picomolar range, which means working concentrations in a cell assay are low, and low concentrations are exactly where adsorption losses bite hardest.
A lipidated peptide at picomolar concentration in an untreated tube is a recipe for an underestimate, and the aggregation question compounds it.
The phase 2 programme published in the Lancet used bodyweight as its primary endpoint and remains the largest published dataset on the compound as a single agent.
It is worth reading for what it establishes and for what it does not, since a dose-ranging trial in humans answers different questions from a receptor assay and the two are frequently quoted as though they were interchangeable.
What Should a Cagrilintide Peptide Certificate Show?
The full sequence, written out, including the position of the lipid attachment and the residues bridged by the disulfide.
Observed mass by spectrometry, since a molecule of this size with a fatty acid chain has a distinctive mass and an incomplete acylation is a real synthesis failure mode.
Purity by chromatography with the method stated.
Aggregate content by size exclusion chromatography, which is the field that separates a useful certificate from a generic one on this compound.
Confirmation that the disulfide is formed rather than reduced, since the free thiol form is a different species that will behave differently.
Net peptide content and the salt form, because the vial mass includes counterion.
Appearance of the reconstituted solution, described rather than assumed.
Lot number and manufacturing date.
A cagrilintide peptide certificate that reports purity without aggregate content has described the covalent chemistry and said nothing about the physical state, and on a molecule engineered specifically for physical stability that is the omission that matters.
How Should the Vial Be Handled?
Handling cagrilintide peptide follows the rules for an aggregation prone sequence, which are stricter than the general ones.
Sealed lyophilized powder holds at minus 20 degrees Celsius. The solid state is where this molecule is most stable, so material that will not be used soon should stay dry.
Bring the vial to ambient temperature before opening, then reconstitute gently by adding diluent down the wall and allowing it to stand.
Do not vortex and do not shake. Agitation drives peptide to the air-liquid interface, and an interface is a nucleation site.
Do not freeze a reconstituted solution. Ice formation concentrates the peptide in the shrinking liquid phase, which is the opposite of what an aggregation prone molecule needs.
Aliquot on first reconstitution so that the working stock is opened once rather than repeatedly.
Use low-binding consumables throughout. A lipidated peptide adsorbs readily and the reported working concentrations are low enough for that to matter.
Run size exclusion chromatography on any stock held longer than a few days, and keep the trace with the record rather than only the conclusion.
Record lot, net peptide content, diluent, storage temperature, the date of reconstitution and the aggregate result if one was measured.
Reconstitution date belongs in that list on this compound specifically, because time in solution is the variable the whole design was built to buy.
Published Literature
Selected references on the design of the analogue, on the aggregation behaviour of the parent hormone, on the published clinical programme and on peptide storage generally.
- Kruse T, Hansen JL, Dahl K, Schaffer L, Sensfuss U, Poulsen C, et al. Journal of Medicinal Chemistry. 2021;64(15):11183-11194. DOI: 10.1021/acs.jmedchem.1c00565
- Westermark P, Andersson A, Westermark GT. Physiological Reviews. 2011;91(3):795-826. DOI: 10.1152/physrev.00042.2009
- Lau DCW, Erichsen L, Francisco AM, Satylganova A, le Roux CW, McGowan B, et al. Lancet. 2021;398(10317):2160-2172. DOI: 10.1016/S0140-6736(21)01751-7
- Manning MC, Chou DK, Murphy BM, Payne RW, Katayama DS. Pharmaceutical Research. 2010;27(4):544-575. DOI: 10.1007/s11095-009-0045-6
Frequently Asked Questions
What is cagrilintide?
Cagrilintide peptide is a long-acting analogue of human amylin, carrying a fatty acid chain and a retained disulfide bridge. It is known in the literature as AM833 and NNC0174-0833, with CAS 1415456-99-3.
What is amylin?
A 37 residue hormone co-secreted with insulin from pancreatic beta cells, also called islet amyloid polypeptide. It is among the best characterised amyloid forming peptides in biology.
Why does human amylin form fibrils?
A stretch in the middle of the human sequence adopts a beta strand conformation readily. Once a few molecules do so together they template the recruitment of more, and growth becomes fast.
Does rodent amylin behave the same way?
No. The rodent sequence carries proline substitutions across the relevant region and does not aggregate comparably, which is why rodent models understate the behaviour.
What did the design have to solve?
Two things pulling against each other. A fatty acid chain extends circulation time but is strongly self-associating, so it had to be added to a peptide that already aggregates without making that worse.
What is a thioflavin T assay?
A fluorescence method for following fibril formation. The dye emits strongly when bound to beta sheet structure, so fluorescence over time traces the conversion of soluble peptide to fibril.
What does the lag time measure?
Nucleation, the slow formation of the first ordered aggregates. The published development work reports a lag near 45 hours at 250 micromolar, which is long for this class at that concentration.
Why is lag time rather than final signal the useful number?
Because growth after nucleation is fast. A long lag says the molecule struggles to start, which is the property that keeps a stock solution usable.
How does aggregation affect an experiment?
Invisibly. Mass and nominal concentration are unchanged while the monomeric fraction falls, so potency is systematically underestimated in a way that resembles ordinary variability.
How is it detected?
Size exclusion chromatography separates aggregate from monomer directly and is the most informative check. Dynamic light scattering is faster. Visual haze appears only once the useful material has largely gone.
Which receptors does it engage?
Both the amylin receptor and the calcitonin receptor, at reported binding figures in the same picomolar range. The two targets are structurally related, so the overlap is expected.
What is the largest published dataset?
The phase 2 dose-ranging programme published in the Lancet in 2021, which used bodyweight as its primary endpoint. It remains the main published work on the compound as a single agent.
Compliance Statement
Cagrilintide is sold exclusively for laboratory research use. It is not a drug, food, or cosmetic product, and it is not a dietary product of any kind. It is not approved by the FDA or any comparable authority for human or veterinary use, it is an investigational compound with no approval as a single agent, it engages two structurally related receptors comparably so published findings cannot be attributed to one of them, its parent hormone is an amyloid forming peptide and aggregation in a prepared solution is invisible to mass-based measurement, and no compound in this range is offered for any human or veterinary purpose. This product is not intended to diagnose, treat, cure, or prevent any disease. It must not be given to humans or animals. Purchase is restricted to qualified researchers and institutions operating within applicable laws. All handling is the responsibility of the purchasing laboratory.
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