GEP44: A 3-in-1 Peptide Designed Around Side Effects

A recent review in Frontiers in Endocrinology pulls together the preclinical case for GEP44, a chimeric peptide stitched from three templates: native GLP-1, exendin-4 (a GLP-1 receptor agonist), and the gut hormone PYY3-36. The reason it stands out is not another set of weight-loss curves. It is the brief the molecule was built to meet.

Across this corner of drug development, the pressure lately has been to chase bigger effects. Tirzepatide and retatrutide, described in the review as the latest wave of GLP-1-containing multi-agonists, work by hitting more than one receptor across linked pathways and, in doing so, drive large, durable weight loss. GEP44 was pointed in a different direction. The priority was gastrointestinal tolerability.

One boundary needs to be set early. GEP44 is experimental, it has no approvals anywhere, and it is not in the Peptra Labs catalogue. Everything discussed here comes from animal work, mostly rodents and shrews. There are no human data.

What GEP44 is

The review characterises GEP44 as a new, monomeric, chimeric peptide derived structurally from GLP-1, exendin-4, and PYY3-36. Functionally, it acts as an agonist at the GLP-1 receptor and across multiple neuropeptide Y receptors.

That “monomeric” detail is not cosmetic. The straightforward alternative for engaging two systems is co-administration, two separate peptides given together. A single chimera pulls both activities into one molecule, which means one pharmacokinetic profile instead of two. Dosing studies become easier to interpret, and manufacturing usually gets simpler as well.

GEP44 traces back to a 2021 Journal of Medicinal Chemistry paper. In that work, the authors describe building monomeric peptide agonists aimed at the GLP-1 receptor and the neuropeptide Y2 receptor, using exendin-4 and PYY3-36 as starting scaffolds. They report selecting GEP44 after in vitro receptor screening, islet insulin-secretion testing, stability assays, and in vivo studies in rats and shrews.

Why PYY3-36 is in the mix

The review’s rationale is basically two-part: add pharmacology, and, ideally, pick up a tolerability benefit.

As the authors frame it, PYY3-36, like GLP-1, is linked with reduced food intake. They also point to evidence that giving a GLP-1 receptor agonist alongside PYY3-36 can produce synergistic drops in food intake and body weight, while achieving similar or even stronger glucose lowering. GEP44 is the one-molecule version of that pairing.

Where the tolerability claim comes from

This is the GEP44 line that tends to travel, so it is worth anchoring it to the primary data.

In the 2021 design paper, the authors report that GEP44 reduced body weight more than exendin-4 in both lean and diet-induced obese rats, and did so without inducing nausea-associated behaviour. They also describe shrew experiments showing near absence of emesis with GEP44, in contrast to exendin-4.

The split between species is practical rather than philosophical. Rats do not vomit, so emesis cannot be measured in them and a species that does is required, and the musk shrew is the standard model used for this. Nausea-linked behaviours in rats and emesis in shrews are proxies for the same clinical issue. They are still proxies, and they are not the clinical outcome.

A point where the review and a primary paper do not line up

This is where the fine print matters.

The review says that, in lean versus diet-induced obese rodents, peripheral GEP44 generally lowers body weight, food intake, and insulin resistance, and increases energy expenditure, with effects similar to or stronger than single GLP-1 receptor agonists.

A 2025 paper in the International Journal of Molecular Sciences, from the same research group that developed GEP44, reports the opposite on the energy-expenditure point. In rats kept on a high-fat diet for at least four months and given GEP44 at 50 nmol/kg, the authors report reductions in energy expenditure, respiratory exchange ratio, core temperature, activity, energy intake, and body weight. Body weight dropped by 3.8 ± 0.2% in males and 2.3 ± 0.4% in females.

Their interpretation is direct: the weight loss looks tied to lowered energy intake, not to increased energy expenditure. They call the energy-expenditure result paradoxical, suggesting it might be secondary to reduced diet-induced thermogenesis, or that it may signal a mechanism that ultimately caps how much weight loss the compound can deliver.

It is possible to read both accounts without assuming either is careless. The review uses “generally” and is summarising across multiple studies and species, while the 2025 paper is one experiment in one model under a defined protocol. Still, anyone quoting the review’s line about increased energy expenditure should be aware that a primary publication from the same lab reports the reverse, and treats it as a potential limit on efficacy rather than a minor aside.

What the evidence is, and what it is not

Three constraints, plainly stated.

First, it is all preclinical: rats, mice, shrews. The review is narrative, not systematic, and it presents no new dataset.

Second, the tolerability comparison is mainly against exendin-4. That is useful for probing mechanism. It is a weak stand-in for a real-world comparison against the drugs people actually take now.

Third, the absolute weight changes in the rat work are modest, 3.8% and 2.3% over a short protocol. That is a mechanistic signal, not a clinical result, and the authors do not present it as one.

Why peptide researchers might care

The pull here is the engineering, not the headline efficacy.

GEP44 is an example of building a single peptide to carry two receptor activities, while putting real weight on what the molecule should not do, namely provoke the kinds of gastrointestinal effects that limit adherence in practice. That is a different design target from the one driving current multi-agonists, and it becomes the more relevant brief if tolerability is the real constraint on uptake.

GEP44 also adds another name to a crowded category that is increasingly difficult to separate analytically. We touched on that issue recently: for nine related compounds, one validated method now identifies nine of them using accurate mass plus fragmentation. GEP44 is not on that list, which is consistent with a compound still sitting in preclinical development.

For labs working with compounds that are available, our documentation for retatrutide reference material and tirzepatide reference material lays out identity and purity fields that multi-agonist studies should establish upfront.

References

• Burmeister MA, Brown SA, Greer JJ, et al. Glucagon-like peptide-1 and peptide YY multi-agonism with GEP44 to optimize weight loss and glycemic control while reducing gastrointestinal side effects: the future of anti-obesity pharmacotherapy?. Frontiers in Endocrinology, 31 July 2026. doi 10.3389/fendo.2026.1925534
• Milliken BT, Elfers C, Chepurny OG, et al. Design and Evaluation of Peptide Dual-Agonists of GLP-1 and NPY2 Receptors for Glucoregulation and Weight Loss with Mitigated Nausea and Emesis. Journal of Medicinal Chemistry, 28 January 2021
• Goldberg M, Blevins JE, Wolden-Hanson T, et al. The Chimeric Peptide (GEP44) Reduces Body Weight and Both Energy Intake and Energy Expenditure in Diet-Induced Obese Rats. International Journal of Molecular Sciences, 26 March 2025

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