Retatrutide (LY3437943): Structure, Receptor Pharmacology and Analysis

Retatrutide (development code LY3437943) is an investigational peptide from Eli Lilly and Company that activates three receptors at once: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). This page is a literature reference. It sets out what is published about the molecule: how it is built, how its receptor activity was characterised, where its regulatory status sits in Canada, and what makes a 39-residue lipidated peptide hard to verify analytically.

Looking for the Canadian status of retatrutide, whether it is legal here and what research-grade material should come with? See our Retatrutide Canada page. This article stays with the science.

This is a reference page, not a product page. Nothing here describes use in people or animals, and nothing here should be read as guidance for any such use.

Is retatrutide approved in Canada?

No. Retatrutide is not authorised by Health Canada for any human or veterinary use. It has no Drug Identification Number (DIN) and no Natural Product Number (NPN). No regulator anywhere has authorised it. It is still an investigational molecule.

The same is true in the United States. In July 2026 Lilly said it plans to submit a Biologics License Application to the FDA in the first quarter of 2027.

Our note on the regulatory status of research peptides in Canada explains how the Food and Drugs Act, DINs and NPNs fit together, and why being described in the literature is not the same as being authorised.

What the molecule is

Retatrutide is a single-chain peptide of 39 amino acids, engineered on a GIP backbone. Lilly’s discovery paper (Coskun et al., 2022) describes three non-coded amino acids built into the sequence, each chosen for a specific job:

• Aib at position 2 (α-aminoisobutyric acid) blocks cleavage by dipeptidyl peptidase-4 (DPP-4), the enzyme that inactivates native GIP and GLP-1 within minutes by removing their first two residues.
• α-methyl-L-leucine at position 13 tunes activity at the glucagon and GIP receptors.
• Aib at position 20 is reported to support GIP receptor activity and pharmacokinetics.

The fourth modification is a C20 fatty diacid, attached through a linker to the lysine at position 17. The diacid binds serum albumin, which slows clearance. That is the same design idea behind other long-acting incretin peptides: the lipid, not the peptide chain, sets how long the molecule lasts.

The formula matches the public PubChem compound record for retatrutide.

Receptor pharmacology

All three target receptors belong to the class B (secretin-family) G-protein-coupled receptors. Each couples mainly to G_s, so activating any of them raises intracellular cyclic AMP. That shared pathway is why cAMP accumulation in cells engineered to express one human receptor at a time is the standard way to measure a molecule like this.

In those assays, Coskun et al. compared retatrutide with each receptor’s own native hormone:

• At the human GIP receptor it was about 8.9 times more potent than native GIP(1-42).
• At the human GLP-1 receptor it was about 2.5 times less potent than GLP-1(7-36) amide.
• At the human glucagon receptor it was about 2.9 times less potent than native glucagon.

In other words, the molecule is biased toward GIP, with GLP-1 and glucagon activity kept within a few-fold of the native hormones. Two cautions apply to any ratio like this. First, the numbers depend on the assay: a binding affinity (K_i) and a functional potency (EC₅₀) are different measurements and cannot be swapped. Second, results at the human receptors do not transfer automatically to the rodent receptors used in animal work. Our explainer on what K_i, IC₅₀ and EC₅₀ actually measure covers why.

Preclinical work

The discovery paper separated each receptor’s contribution using genetically modified mice: wild-type animals were compared with GLP-1 receptor-null and GIP receptor-null strains, so any response that survived a knockout could be credited to the receptors that remained. C57BL/6 mouse models were used for in vivo pharmacology, and cynomolgus monkeys for toxicology.

That knockout design is the useful lesson for anyone working with multi-receptor peptides. A molecule that hits three receptors produces one combined response, and only receptor-deleted systems, or selective antagonists, can show how much each receptor contributes.

Why this molecule is hard to verify analytically

Length and lipidation make retatrutide one of the harder peptides to confirm by the usual certificate-of-analysis methods. Four things matter:

1. Deletion sequences hide easily. Every residue is another synthesis cycle and another chance for a coupling to fail. Losing one internal residue from a 39-residue, 4,731 g/mol chain is a mass change of only a few percent. A low-resolution instrument can miss it, and a truncated chain often elutes almost alongside the full one.
2. The lipid dominates reversed-phase HPLC. The C20 diacid makes retention depend mostly on the lipid. Impurities that share the lipid but differ in the peptide chain can co-elute with the main peak, so a single high HPLC area percentage is a weaker purity guarantee here than for a short unmodified peptide.
3. Identity needs the intact mass. For this class, mass spectrometry confirming the intact molecule at about 4,731 g/mol matters more than the purity figure. A certificate that reports HPLC purity without a mass result leaves identity unconfirmed.
4. Non-coded residues complicate sequencing. Aib and α-methyl-leucine are not standard residues, so sequence confirmation by fragmentation needs reference data that allows for them.

Our notes on where peptide impurities come from and how to read a certificate of analysis go into both problems, and storage and stability of lyophilised peptides covers handling.

Questions people ask about retatrutide in Canada

Is retatrutide legal in Canada? Retatrutide is not authorised by Health Canada as a drug, so it cannot be sold in Canada as a medicine or for human use. It has no DIN or NPN. Our note on the regulatory status of research peptides in Canada sets out how the Food and Drugs Act treats unauthorised molecules.

How is retatrutide different from semaglutide and tirzepatide? Semaglutide is a GLP-1 analogue that acts on one receptor. Tirzepatide acts on the GIP and GLP-1 receptors. Retatrutide adds the glucagon receptor, making it a triple agonist. Tirzepatide and retatrutide are both 39-residue, GIP-based molecules from Lilly carrying a C20 fatty diacid.

How is retatrutide purity tested? By reversed-phase HPLC for purity and mass spectrometry for identity. For this molecule the intact mass, about 4,731 g/mol, is the more important of the two, for the reasons set out above.

References

1. Coskun T, Urva S, Roell WC, et al. Discovery and characterisation of LY3437943 (receptor pharmacology and preclinical studies). Cell Metab. 2022;34(9):1234-1247. doi:10.1016/j.cmet.2022.07.013
2. PubChem compound record: Retatrutide.

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