Retatrutide (LY3437943) is a synthetic, lipidated 39-residue peptide that acts as an agonist at three class B G protein-coupled receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). It is used as a reference triple agonist in receptor pharmacology and in analytical work on lipidated peptides. NuVion supplies Retatrutide as a laboratory chemical for in vitro research use only.
Key facts
| Type/class | Synthetic lipidated peptide, GIPR/GLP-1R/GCGR triple agonist |
| Amino acid count | 39, C-terminal amide |
| Molecular formula | C221H342N46O68 |
| Molecular weight | 4731.3 g/mol |
| CAS number | 2381089-83-2 |
| Synonyms/other names | LY3437943, LY-3437943, GIP/GLP-1/glucagon receptor triple agonist |
| Supplied form | Lyophilised powder in a sealed vial |
Retatrutide
From $129 AUD
View productResearch use only. Not for human or veterinary use.
Structure and chemistry
The backbone of retatrutide is built on the native GIP sequence, with residues swapped in from glucagon and GLP-1 so that a single chain fits the orthosteric pocket of all three receptors. Tyr1 and the Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile stretch at positions 4 to 12 carry the shared N-terminal recognition motif of the glucagon peptide family, while the C-terminus ends in the Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser extension derived from exendin-4, which stabilises the C-terminal helix.
Four non-natural features define the molecule. Alpha-aminoisobutyric acid (Aib) replaces the residue at position 2, which blocks cleavage by dipeptidyl peptidase-4 between residues 2 and 3. A second Aib sits at position 20, and alpha-methyl-L-leucine at position 13 increases helical propensity through the middle of the chain. The side chain of Lys17 carries a C20 fatty diacid attached through a hydrophilic linker. That diacid binds serum albumin, and in assays it means the free peptide concentration depends on the albumin content of the medium. The C-terminus is amidated. With several glutamates and aspartates and no methionine or cysteine, the peptide carries a net negative charge at neutral pH, is least soluble near its isoelectric point in the mildly acidic range, and is chemically stable against oxidation, though the Gln residues and the Asp-Tyr bond are the usual sites of slow deamidation and hydrolysis.
Mechanism of action
GIPR, GLP-1R and GCGR are class B1 GPCRs that couple mainly to Gs. Agonist binding uses the two-domain model: the C-terminal half of the peptide docks into the extracellular domain and the N-terminal half inserts into the transmembrane bundle, which triggers Gs activation, adenylyl cyclase stimulation and a rise in intracellular cAMP. Downstream, protein kinase A phosphorylates CREB and other targets, and the exchange protein Epac2 is activated in parallel. Receptor phosphorylation, beta-arrestin recruitment and internalisation follow, and the extent of each varies with the ligand.
Retatrutide activates all three receptors in cAMP accumulation assays run in HEK293 cells expressing each human receptor individually. Its potency profile is deliberately unequal: activity at GIPR is close to that of native GIP, while potency at GLP-1R and at GCGR is lower than that of native GLP-1 and glucagon. This is the intended balance of the design and is the reason the compound is characterised on all three receptors side by side. Beta-arrestin recruitment and internalisation assays are used to define its signalling profile at each receptor, in the same way as for tirzepatide, where reduced arrestin recruitment at GLP-1R relative to native GLP-1 was reported.
At the cellular level the three receptors sit on different cell types. In pancreatic beta-cell lines such as INS-1 and MIN6, GIPR and GLP-1R activation raises cAMP and potentiates glucose-stimulated insulin secretion, which is the standard functional readout for incretin receptor agonists. In hepatocyte cultures, GCGR activation raises cAMP, activates PKA, drives glycogen phosphorylase and increases transcription of the gluconeogenic enzymes PEPCK and glucose-6-phosphatase through CREB. In cultured adipocytes, GIPR signalling changes lipoprotein lipase activity and lipid handling. Each of these is measured in isolation in vitro, and the compound’s value is that the same molecule can be applied across all of them.
Research applications
Retatrutide sits in the Metabolism category and is used in the following kinds of work.
- cAMP accumulation assays (HTRF or luminescence) in HEK293 or CHO cells expressing human GIPR, GLP-1R or GCGR, with native GIP, GLP-1 and glucagon as comparators.
- Competition binding with radiolabelled or fluorescent ligands at each receptor.
- Beta-arrestin recruitment and receptor internalisation assays to map signalling bias.
- Glucose-stimulated insulin secretion assays in INS-1 832/13 or MIN6 beta-cell lines.
- Hepatocyte cAMP and glycogenolysis assays for GCGR activity.
- Analytical work on lipidated peptides, including RP-HPLC method development, LC-MS identity confirmation, albumin binding by ultrafiltration or SPR, and DPP-4 stability assays in vitro.
Handling in the laboratory
The lyophilised peptide is reconstituted with bacteriostatic water added down the side of the vial and swirled until clear. The reconstitution calculator gives the volume for a chosen stock concentration from the vial content. Lipidated peptides self-associate in water and adsorb to untreated plastic, so stock solutions are kept in low-binding tubes and diluted into assay buffer or medium immediately before use. Solubility is lowest in the mildly acidic range, so neutral to slightly basic buffers are used for dilution, and the albumin or serum content of the assay medium is recorded because it shifts the free concentration.
Unopened vials are kept sealed, dry, away from light and refrigerated as described in the product documentation. Reconstituted solution is refrigerated and used within the period given in that documentation. The compound is characterised by RP-HPLC for purity and by mass spectrometry for identity. Because the fatty diacid makes the peptide strongly retained on C18, gradients for in-house checks run to a higher organic content than for unmodified peptides of similar length.
Testing and supply from NuVion
Retatrutide from NuVion is made by a GMP-audited manufacturer and supplied lyophilised in sealed vials. Most batches are independently tested by Janoshik Analytical for purity by RP-HPLC and identity by mass spectrometry, and the Certificate of Analysis for a tested batch is published on the product page and in the Certificates of Analysis library. Orders are dispatched from within Australia.
Related compounds
The closest comparator in the same category is Tirzepatide, a lipidated dual GIPR and GLP-1R agonist built on the same GIP backbone, and MOTS-c is used alongside it in AMPK and cellular metabolism assays.
Frequently asked questions
What is retatrutide used for in research?
It is used as a reference triple agonist for GIPR, GLP-1R and GCGR in cAMP, binding, arrestin recruitment and internalisation assays, and as a stimulus in beta-cell and hepatocyte signalling experiments. It is also a useful model compound for analytical work on lipidated peptides.
How is retatrutide supplied?
As a lyophilised powder in a sealed vial. Purity is determined by RP-HPLC and identity by mass spectrometry, and a Certificate of Analysis for a tested batch is available on the product page.
Is retatrutide a therapeutic good in Australia?
No. Retatrutide from NuVion is a laboratory chemical for in vitro research. It is not included in the Australian Register of Therapeutic Goods and has not been assessed by the Therapeutic Goods Administration.
How should retatrutide be stored?
Keep the sealed vial dry, away from light and refrigerated as set out in the product documentation. After reconstitution, keep the solution refrigerated in a low-binding tube, avoid acidic buffers where it is least soluble, and use it within the period stated in the documentation.
Research use only. This product is a laboratory chemical supplied for in vitro research. It is not included in the Australian Register of Therapeutic Goods and has not been assessed by the Therapeutic Goods Administration for quality, safety or efficacy. It is not for human or veterinary use, and nothing on this page is a representation about therapeutic use.
