Retatrutide is a synthetic 39-amino-acid peptide, known in the development literature as LY3437943, that acts as a single-molecule agonist at three receptors at once: GLP-1R, GIPR and the glucagon receptor (GCGR). This retatrutide research peptide guide covers its structure, receptor pharmacology, the published trial programme, molecular specifications and laboratory handling. It is written for researchers, analytical chemists and procurement staff working with lyophilised material under research-use-only terms.
Key takeaways
- Retatrutide (LY3437943) is a triple agonist — it activates GLP-1R, GIPR and GCGR from one peptide backbone, unlike mono-agonists (semaglutide) or dual agonists (tirzepatide).
- Molecular specification: CAS 2381089-83-2, formula C221H342N46O68, average molecular weight approximately 4,731 Da, 39 residues, C-terminally amidated.
- Long circulating time comes from a C20 diacid fatty-acid chain attached through a γGlu–AEEA linker, which drives reversible albumin binding.
- Two α-aminoisobutyric acid (Aib) substitutions and an α-methyl-leucine confer resistance to dipeptidyl peptidase-4 and to proteolysis.
- Published in-vitro potency is highest at GIPR, intermediate at GLP-1R and weakest at GCGR — the glucagon arm is deliberately the least potent of the three.
- The distinguishing feature versus dual agonists is the glucagon arm, which is described in the literature as adding an energy-expenditure and hepatic-lipid component to the incretin appetite and glycaemic arms.
- Supplied as a lyophilised powder for laboratory research only; store the sealed vial at −20 °C and protect from light and moisture.
What is retatrutide?
Retatrutide is a synthetic peptide agonist that binds and activates three class B G-protein-coupled receptors — the glucagon-like peptide-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon receptor (GCGR). It was described in the peer-reviewed literature in 2022 under the development code LY3437943.
The molecule is a 39-residue chain built on an incretin-like scaffold. Its sequence is derived conceptually from GIP rather than from GLP-1, which is a point worth noting because it explains why the compound’s highest in-vitro potency sits at the GIP receptor. Chemically it belongs to the same family as tirzepatide: a lipidated, protease-stabilised, long-acting incretin analogue.
In a research setting, retatrutide is of interest because it lets investigators probe what happens when a catabolic signal (glucagon) is layered onto two anabolic-glycaemic signals (GLP-1 and GIP) in a single, pharmacokinetically matched molecule. Prior to single-molecule triple agonists, that question could only be approached by co-administering separate compounds with different clearance profiles.
How the triple agonist mechanism works
Retatrutide’s mechanism is described as simultaneous agonism at three related class B GPCRs, each coupling primarily to Gs and raising intracellular cyclic AMP. The pharmacological logic is that GLP-1R and GIPR contribute glucose-dependent insulinotropic and appetite-related signalling, while GCGR contributes a catabolic, energy-expenditure signal that the incretin receptors do not.
The three receptors share a common architecture: a large extracellular domain that captures the peptide’s C-terminal helix, and a seven-transmembrane bundle whose core receives the peptide’s N-terminus. Cryo-electron microscopy work published in Cell Discovery in 2024 resolved retatrutide bound to all three receptors and reported that the peptide adopts a single continuous helix penetrating the transmembrane core in each case.
Why one molecule can hit three receptors
That structural study reported the three complexes are highly similar overall, with conserved salt bridges to acidic residues in transmembrane helices 6 and 7 preserved across all three. The receptor-specific differences sit mainly in extracellular loop 1 and in the position of transmembrane helix 7. Retatrutide’s middle region — roughly residues 10 to 21 — showed the greatest conformational variation between complexes, which the authors identified as the region where selectivity could be tuned.
This matters for anyone interpreting assay data: the three arms are not independent switches. A single conformational change in the peptide’s mid-region alters the balance between all three receptors simultaneously, which is why triple agonist structure–activity work is considerably harder than mono-agonist work.
The glucagon arm and why it is deliberately weakest
Glucagon receptor agonism raises hepatic glucose output, which works against the glycaemic effect of the incretin arms. The published design solution is potency imbalance: the glucagon arm is set at a much lower relative potency than the incretin arms, so that at circulating concentrations the incretin signalling dominates glycaemic control while the glucagon signalling contributes to energy expenditure and hepatic lipid handling.
Retatrutide structure and modifications
Retatrutide is a 39-residue, C-terminally amidated peptide carrying four engineering features: two α-aminoisobutyric acid (Aib) substitutions, one α-methyl-leucine, and a single lysine bearing a C20 diacid fatty-acid chain attached through a γ-glutamate and AEEA (2-[2-(2-aminoethoxy)ethoxy]acetyl) spacer.
The four engineering features
- Aib at position 2. α-aminoisobutyric acid is a non-proteinogenic, doubly methylated alanine. Placed at the second residue it blocks cleavage by dipeptidyl peptidase-4, the enzyme that inactivates native GLP-1 and GIP within minutes.
- α-methyl-leucine in the mid-chain. A second backbone-methylated residue that stiffens the helix and adds resistance to general proteolysis.
- Aib in the C-terminal half. A further helix-stabilising substitution that supports the continuous-helix conformation seen in the cryo-EM structures.
- C20 diacid acylation via γGlu–AEEA. The eicosanedioic acid chain binds reversibly to circulating albumin. Albumin acts as a depot, slowing renal clearance and extending the plasma half-life into the multi-day range that supports once-weekly administration in trial protocols.
- C-terminal amidation. Removing the free carboxylate at the C-terminus removes a charge and a carboxypeptidase substrate, a standard stabilising modification in incretin analogues.
Molecular specifications and identity data
Analytical identity for retatrutide rests on three numbers: the CAS registry number, the molecular formula and the average molecular weight. A certificate of analysis should report an observed mass consistent with the calculated average mass, alongside a chromatographic purity figure.
| Parameter | Value | Note |
|---|---|---|
| Common name | Retatrutide | INN |
| Development code | LY3437943 | Used throughout the primary literature |
| CAS registry number | 2381089-83-2 | Free peptide |
| Molecular formula | C221H342N46O68 | Includes the C20 diacid and linker |
| Average molecular weight | ≈ 4,731.3 Da | Free peptide, not the acetate salt |
| Chain length | 39 amino acids | C-terminally amidated |
| Non-standard residues | Aib ×2, α-methyl-leucine ×1 | Protease resistance |
| Lipidation | C20 diacid via γGlu–AEEA on Lys | Albumin binding |
| Receptor targets | GLP-1R, GIPR, GCGR | Class B GPCRs, Gs/cAMP coupled |
| Physical form supplied | White to off-white lyophilised powder | Sealed vial, research use only |
| Typical solubility for lab work | Sterile or bacteriostatic water | Prepare as stock solution |
Receptor potency and selectivity
In cell-based cyclic AMP accumulation assays, retatrutide’s reported half-maximal effective concentrations differ substantially between the three receptors. Published in-vitro values place GIPR as the most potently engaged target, GLP-1R intermediate, and GCGR roughly an order of magnitude weaker than GLP-1R.
Two caveats apply when comparing these numbers to your own assay data. First, EC50 values are strongly dependent on receptor expression level and the host cell line, so absolute values from different laboratories are rarely directly comparable. Second, in the presence of albumin the free fraction of an acylated peptide is very low, which shifts apparent potency in serum-containing media relative to serum-free conditions.
What the published research programme reported
Retatrutide has been the subject of a substantial peer-reviewed programme, from molecular discovery through phase 2. The material below describes what was published in clinical trial programmes for the investigational pharmaceutical form; it is provided as research context and is not a description of what any GenoPept product does.
| Publication | Type | What was reported |
|---|---|---|
| Coskun et al., Cell Metabolism, 2022 | Discovery and first-in-human | Molecular design of LY3437943, receptor pharmacology, rodent efficacy and initial human pharmacokinetics supporting weekly administration. |
| Urva et al., The Lancet, 2022 | Phase 1b, multiple ascending dose | Safety, tolerability and pharmacodynamics over repeated administration in participants with type 2 diabetes. |
| Jastreboff et al., NEJM, 2023 | Phase 2, obesity (NCT04881760) | 338 participants randomised across placebo and 1, 4, 8 and 12 mg weekly. Mean weight reduction up to 17.5% at 24 weeks and up to 24.2% at 48 weeks in the highest group. |
| Rosenstock et al., The Lancet, 2023 | Phase 2, type 2 diabetes | Randomised, placebo- and active-controlled trial of retatrutide in people with type 2 diabetes, reporting glycaemic and body-weight outcomes. |
| Urva et al., Diabetes, Obesity and Metabolism, 2023 | Mechanistic sub-study | Retatrutide delays gastric emptying, consistent with the GLP-1 receptor arm of its pharmacology. |
| Li et al., Cell Discovery, 2024 | Structural biology | Cryo-EM structures of retatrutide bound to GLP-1R, GIPR and GCGR at 2.68–3.26 Å, defining the conserved and receptor-specific contacts. |
For a laboratory buyer, the practical value of this literature is that retatrutide is unusually well characterised for a compound in this class. Both its molecular structure and its receptor-level behaviour have been published in peer-reviewed journals, which gives analytical staff a firm basis for identity confirmation and assay design.
Retatrutide vs tirzepatide and semaglutide
The three compounds sit on a ladder of receptor coverage: semaglutide is a GLP-1 mono-agonist, tirzepatide a GIP/GLP-1 dual agonist, and retatrutide a GIP/GLP-1/glucagon triple agonist. All three share the same core stabilisation strategy — Aib substitution plus fatty-diacid acylation for albumin binding.
| Property | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Class | Mono-agonist | Dual agonist | Triple agonist |
| GLP-1R | Yes | Yes | Yes |
| GIPR | No | Yes | Yes |
| GCGR | No | No | Yes |
| Backbone origin | GLP-1(7-37) | GIP-based | GIP-based |
| Chain length | 31 residues | 39 residues | 39 residues |
| CAS number | 910463-68-2 | 2023788-19-2 | 2381089-83-2 |
| Molecular formula | C187H291N45O59 | C225H348N48O68 | C221H342N46O68 |
| Approx. average MW | 4,113.6 Da | 4,813.5 Da | 4,731.3 Da |
| Fatty-acid chain | C18 diacid | C20 diacid | C20 diacid |
| C-terminus | Free acid | Amide | Amide |
The head-to-head comparison is treated in detail in our semaglutide vs tirzepatide vs retatrutide comparison. In short, moving from one receptor to three widens the pharmacological question being asked but also multiplies the number of confounds in any experiment — a triple agonist is not a cleaner tool than a mono-agonist, it is a broader one.
Reconstitution and solution concentrations
Retatrutide is supplied as a lyophilised cake. To prepare a laboratory stock solution, add diluent slowly down the inside wall of the vial and allow the cake to dissolve without agitation. The table below is a concentration reference for solution preparation, not a dosing schedule.
- Equilibrate. Allow the sealed vial to reach room temperature before opening. Reconstituting a cold vial invites condensation onto the powder.
- Sanitise. Wipe the rubber stopper of both the peptide vial and the diluent vial with 70% isopropyl alcohol and let them dry.
- Add diluent slowly. Draw the chosen volume of bacteriostatic or sterile water and let it run down the vial wall. Do not inject the stream directly onto the cake.
- Dissolve without shaking. Swirl gently or leave the vial to stand. Vortexing and vigorous shaking cause shear and foaming, which can drive aggregation in acylated peptides.
- Inspect. The solution should be clear and free of visible particulates. Cloudiness or fibrous material indicates aggregation.
- Label and refrigerate. Record compound, batch, concentration and date, then store at 2–8 °C protected from light.
| Peptide in vial | Diluent added | Resulting concentration | Amount per 0.1 mL | Approx. molarity |
|---|---|---|---|---|
| 5 mg | 1 mL | 5 mg/mL | 500 mcg | ≈ 1.06 mM |
| 5 mg | 2 mL | 2.5 mg/mL | 250 mcg | ≈ 528 µM |
| 10 mg | 1 mL | 10 mg/mL | 1,000 mcg | ≈ 2.11 mM |
| 10 mg | 2 mL | 5 mg/mL | 500 mcg | ≈ 1.06 mM |
| 10 mg | 3 mL | 3.33 mg/mL | 333 mcg | ≈ 704 µM |
| 15 mg | 3 mL | 5 mg/mL | 500 mcg | ≈ 1.06 mM |
Molarity figures assume the stated label mass is free peptide at MW 4,731.3 Da. Correct for net peptide content from the certificate of analysis where exact molar concentration matters. Full method detail is in our peptide reconstitution guide.
Storage, stability and quality verification
Lyophilised retatrutide is stable for extended periods when kept sealed, cold and dry. Once in solution, stability drops sharply — the peptide is exposed to hydrolysis, oxidation and surface adsorption, and the acylated chain increases the tendency to adsorb to plastic and glass surfaces.
Practical storage guidance
Lyophilised, unopened
Store at −20 °C in the sealed vial, protected from light. Short periods at 2–8 °C during transit are normal and are accounted for in supplier stability data. Keep desiccated; moisture ingress is the main enemy of a lyophilised cake.
Reconstituted solution
Refrigerate at 2–8 °C and use within a short working window. For longer storage, aliquot into low-binding tubes and freeze at −20 °C or below to avoid repeated freeze–thaw cycles, which promote aggregation in lipidated peptides.
Quality verification for a peptide of this complexity requires two orthogonal measurements. Reverse-phase HPLC gives the chromatographic purity — the proportion of UV-absorbing material eluting as the main peak. Mass spectrometry confirms identity by matching the deconvoluted mass to the calculated average mass. Neither alone is sufficient: HPLC cannot distinguish a co-eluting isomer, and MS cannot quantify a truncation that ionises differently. Both appear on a complete certificate of analysis, viewable at our COA page.
Retatrutide in the GenoPept store
Frequently asked questions
What is retatrutide?
Retatrutide, also known as LY3437943, is a synthetic 39-amino-acid peptide that acts as a triple agonist at the GLP-1, GIP and glucagon receptors. It carries a C20 fatty-diacid chain for albumin binding and two Aib substitutions for protease resistance. GenoPept supplies it as a lyophilised powder strictly for laboratory research use.
What is the molecular weight of retatrutide?
The average molecular weight of retatrutide as a free peptide is approximately 4,731.3 Da, corresponding to the molecular formula C221H342N46O68. Its CAS registry number is 2381089-83-2. Note that material supplied as an acetate salt will have a higher gross mass than the free peptide, which is why net peptide content is stated separately on a certificate of analysis.
How is retatrutide different from tirzepatide?
Both are 39-residue, C20-acylated, GIP-based analogues, but tirzepatide activates two receptors (GIPR and GLP-1R) while retatrutide activates three, adding the glucagon receptor. That third arm is described in the literature as contributing an energy-expenditure and hepatic-lipid component. Retatrutide’s glucagon potency is deliberately the weakest of its three arms.
Why does retatrutide have a fatty acid attached?
The C20 diacid chain, linked through a γ-glutamate and AEEA spacer on a lysine side chain, binds reversibly to serum albumin. Albumin acts as a circulating reservoir that slows renal filtration and enzymatic clearance, extending the plasma half-life from minutes to days. The same strategy is used in semaglutide and tirzepatide.
Does retatrutide need to be refrigerated?
The sealed lyophilised vial is best kept at −20 °C, protected from light and moisture; short periods at 2–8 °C during shipping are normal. Once reconstituted, the solution should be refrigerated at 2–8 °C and used within a short working window, or aliquoted and frozen to avoid repeated freeze–thaw cycles.
What does a retatrutide certificate of analysis show?
A complete COA reports appearance, identity by mass spectrometry (observed mass matched to the calculated average mass), chromatographic purity by reverse-phase HPLC, net peptide content, water content and the batch number. Identity and purity are separate measurements and both are needed — see our peptide purity testing guide for how to read each section.
Is retatrutide an approved medicine?
No. At the time of writing retatrutide is an investigational compound that has been studied in published phase 2 and phase 3 clinical trial programmes but is not a licensed medicine. The material supplied by GenoPept is a research chemical for in-vitro laboratory work and is not a medicine, not for human or veterinary use, and not for diagnosis or treatment.
Can retatrutide be combined with cagrilintide in research?
Combinations of an incretin agonist with an amylin analogue are an active area of published research, most extensively for cagrilintide with semaglutide. GenoPept stocks a retatrutide plus cagrilintide blend as a single lyophilised vial for laboratory work. There is no peer-reviewed clinical literature specific to that particular pairing, so any laboratory work with it is exploratory.
References
- Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metabolism. 2022. PubMed
- Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. The Lancet. 2022. PubMed
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. New England Journal of Medicine. 2023. PubMed
- Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet. 2023;402(10401):529–544. PubMed
- Li W, Zhou Q, Cong Z, et al. Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. Cell Discovery. 2024;10:77. Cell Discovery
- Urva S, Coskun T, Kadaba Sridharan S, et al. The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying. Diabetes, Obesity and Metabolism. 2023. Publisher
Research-grade retatrutide, batch-verified
GenoPept supplies retatrutide as lyophilised vials with a per-batch third-party certificate of analysis covering HPLC purity and mass spectrometry identity, dispatched from the UK, strictly for laboratory research.