LY3437943 Research

LY3437943 is a single synthetic peptide that activates three closely related receptors. It is a triple agonist peptide: a GIP, GLP-1 and glucagon receptor agonist in a single chain. This account of LY3437943 research covers how the chain is built, what each modification is for, how the receptors respond, and what structural, tissue and animal studies report.

What the molecule is built from

The peptide carries 39 residues and ends in an amide rather than a free acid. It is built on a GIP peptide backbone [1]. The sequence is Y-Aib-Q-G-T-F-T-S-D-Y-S-I-αMeL-L-D-K-K*-A-Q-Aib-A-F-I-E-Y-L-L-E-G-G-P-S-S-G-A-P-P-P-S-NH2.

Three of those positions are not standard coded residues. Aib, or 2-aminoisobutyric acid, sits at positions 2 and 20, and α-methyl-L-leucine sits at position 13. The lysine written as K* is residue 17, and it carries the acyl chain described below.

The molecular formula is C221H342N46O68 and the molecular weight is 4731.3 g/mol. The compound is indexed under CAS 2381089-83-2 and UNII NOP2Y096GV. Several PubChem records carry this CAS, so the CAS and UNII are the practical identifiers. Material supplied for laboratory work, such as Pure-RTA-3, carries its own analytical data alongside these published identifiers.

Why each modification is there

The discovery paper gives a reason for each engineered position [1].

• Aib at position 2. Dipeptidyl peptidase-4 clips the first two residues from native incretin chains. Aib here provides stability against that cleavage [1].
• α-methyl-L-leucine at position 13. The paper reports that it contributes to optimal glucagon and GIP receptor activity [1].
• Aib at position 20. The paper credits it with optimal GIP activity, the pharmacokinetic profile and developability, meaning how practical the molecule is to manufacture and formulate [1].
• The lysine 17 side chain. K17 carries one AEEA spacer unit, then γ-glutamic acid, then eicosanedioic acid, a 20-carbon fatty diacid. The paper describes it as enabling albumin binding, a strategy to extend the half-life [1].

What LY3437943 research shows at the three receptors

The GIP, GLP-1 and glucagon receptors are class B1 G protein-coupled receptors. All three couple to Gs and raise intracellular cAMP when activated.

The discovery paper measured cAMP accumulation in HEK293 cell lines, each engineered to express one human receptor [1]. LY3437943 was 2.9-fold less potent than native glucagon at the glucagon receptor, and 2.5-fold less potent than native GLP-1 at the GLP-1 receptor [1]. At the GIP receptor it was 8.9-fold more potent than native GIP [1]. The paper sums this up as balanced glucagon and GLP-1 receptor activity, with more activity at the GIP receptor [1]. It was also potent at the mouse versions of all three receptors, which matters for reading the mouse work [1].

These are cell-based measurements, and receptor density in an engineered line is artificial. They show signaling at each receptor, not how the three activities combine in a living animal.

What the cryo-EM structures show

A structural report, published as a letter, resolved the peptide bound to each of the three receptors in complex with Gs protein [2]. In all three, residues 1 to 13 reach into the core of the receptor's transmembrane domain [2]. Residues 14 to 30 contact the extracellular domain, the outer tip of the first transmembrane helix and the first extracellular loop [2].

The report credits the triple activity to contacts shared by all three receptors, plus receptor-specific contacts, mostly in the upper half of the binding pocket [2]. The same group measured cAMP responses to the peptide at normal and mutated receptors in cells. Mutating several contact residues lowered its potency, which ties the structures to activity [2].

A structure is one captured state of a complex prepared for imaging, so it reports geometry rather than activity over time.

Isolated heart tissue

Two reports from one laboratory tested the peptide in isolated atrial tissue, kept alive in an organ bath with no circulation and no nerve input [3] [4]. That isolates the tissue's own response, but an isolated atrium is not a working heart.

In electrically paced mouse left atria, the peptide did not increase the force of contraction, although a beta-adrenoceptor agonist run for comparison did [3]. In spontaneously beating mouse right atria, it raised the beating rate [3]. A glucagon receptor antagonist blocked that rise, and the authors traced it to the glucagon receptor, cAMP and protein kinase A [3].

The second report used strips of human right atrium removed during heart surgery. That is laboratory work on donated human tissue, not a study in people. There, the peptide increased the force of contraction [4]. Antagonists at each of its three receptors reduced that effect, and the authors concluded that it acted through its own receptors and the cAMP system [4].

So force rose in human atrial tissue but not in mouse left atria. Each finding belongs to the species that produced it.

Animal studies

The discovery paper measured body weight, calorie intake, energy expenditure and blood glucose in obese mice [1]. A study run by two contract research companies used diet-induced obese mouse and hamster models of fatty liver disease. It measured body weight and composition, food intake, an insulin-resistance index, blood lipids and liver fat [5]. Its authors work for those companies, and two of them hold shares in one [5].

A university group, using purchased material, implanted pancreatic or lung tumor cells in obese mice [6]. It measured tumor take, onset and growth, and immune cell populations [6].

Each animal finding describes the model it came from, and none transfers to people.

How it is broken down and cleared in laboratory species

The discovery paper describes the C20 diacid on lysine 17 as an albumin-binding strategy to extend the half-life [1]. It also credits Aib at position 20 with part of the pharmacokinetic profile [1]. It characterized the peptide's pharmacokinetics in mice, but reports those data only in its supplement [1]. This article gives no breakdown or excretion figures for laboratory species.

Human research

Human clinical studies of LY3437943 have been published. This article does not summarize them. It covers what laboratory research has measured about the molecule itself: its structure, its receptor activity, and what cell, tissue and animal studies report.

What the evidence covers

Much of the laboratory literature on this molecule comes from the developer's own scientists [1]. One group's assay conditions shape those numbers. The structural, heart-tissue and later animal reports cited here come from groups outside the developer [2] [3] [4] [5] [6].

The laboratory record is still young: one structural report, two heart-tissue reports from one laboratory and three animal reports. Activity at all three receptors has been measured by two separate groups, and one of them also resolved the bound structures [1] [2].

Conclusion

LY3437943 is a 39-residue, amidated, fatty-acylated peptide built on a GIP backbone. Cell assays report agonism at three receptors, strongest relative to the native hormone at the GIP receptor, and cryo-EM shows how one chain fits three pockets. Heart tissue from two species gave different answers. None of it answers a question about people.

References

1. 1

   Coskun T, Urva S, Roell WC, et al. Cell Metab. 2022;34(9):1234-1247.e9. PMID 35985340
2. 2

   Li W, Zhou Q, Cong Z, et al. Cell Discov. 2024;10(1):77. PMID 39019866
3. 3

   Neumann J, Ahlrep U, Hofmann B, et al. Naunyn Schmiedebergs Arch Pharmacol. 2025;398(12):17147-17160. PMID 40464942
4. 4

   Neumann J, Ahlrep U, Hofmann B, et al. Naunyn Schmiedebergs Arch Pharmacol. 2026;399(1):317-327. PMID 40613938
5. 5

   Briand F, Le Cudennec C, Grasset E, et al. Obesity (Silver Spring). 2026;34 Suppl 1(Suppl 1):43-53. PMID 41741376
6. 6

   Marathe SJ, Grey EW, Bohm MS, et al. NPJ Metab Health Dis. 2025;3(1):10. PMID 40094000