PE-22-28 Research, Specifications & Scientific Information

Introduction

PE-22-28 is seven amino acids long and exists because a longer peptide fell apart too quickly. Its parent, spadin, is a 17-residue fragment released when the precursor of the neurotensin receptor-3 — sortilin — is processed, and it was described in 2010 as the first natural peptide characterised as an antidepressant, acting by blocking the TREK-1 potassium channel ^[3]. Spadin's reported activity in mice did not persist beyond about seven hours ^[4]. The same laboratory examined what spadin broke down into in blood, and built a shorter peptide from the answer ^[1].

The result is unusual in the direction of its outcome. Shortening a peptide usually costs potency. Here the reported half-maximal inhibitory concentration at TREK-1 fell from 40–60 nM for spadin to 0.12 nM for the seven-residue analogue, while the reported duration of action in rodents rose from roughly seven hours to roughly twenty-three ^[1].

What has not happened is equally important. There is no human study of this compound, no registered trial of it or of spadin, and almost no work on it outside the group that made it. This page reports the preclinical record as it stands and does not extend it.

What Is PE-22-28?

PE-22-28 is a synthetic heptapeptide with the sequence Gly-Val-Ser-Trp-Gly-Leu-Arg. PubChem holds it as compound identifier 165437303 under CAS registry number 1801959-12-5.

The name is positional rather than descriptive. Sortilin, also called neurotensin receptor-3, is synthesised as a precursor whose maturation releases a propeptide; spadin is the portion of that propeptide spanning residues 12 to 28, hence its alternative designation PE 12-28 ^[3]. PE-22-28 spans residues 22 to 28 of the same propeptide — the C-terminal seven residues of spadin. It is also called mini-spadin in the later papers from the originating group ^[2].

It is a research compound and nothing else. It is not approved by the U.S. Food and Drug Administration for any indication, no marketing application for it is on record in the United States, and no clinical trial of it is registered anywhere.

PE-22-28 Specifications

PubChem carries the peptide under compound identifier 165437303 with CAS registry number 1801959-12-5, molecular formula C35H55N11O9 and average mass 773.9 g/mol; the same record lists an acetate salt form, and material supplied as a reagent is commonly an acetate or trifluoroacetate salt whose mass differs accordingly. The name encodes the molecule's origin: spadin is designated PE 12-28 after its position in the propeptide released when the neurotensin receptor-3 / sortilin precursor is processed, and PE 22-28 is the seven-residue C-terminal portion of that fragment. Comparing the two PubChem structures confirms the relationship — spadin's C-terminal seven residues are Gly-Val-Ser-Trp-Gly-Leu-Arg, which is this peptide in full. Several N- and C-terminally modified derivatives are described in the originating paper and are distinct substances from the unmodified heptapeptide.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does PE-22-28 Work?

The target is TREK-1, the two-pore-domain potassium channel encoded by KCNK2.

TREK-1 became a target in depression research through a genetic observation rather than a pharmacological one: mice in which the TREK-1 gene is deleted show a phenotype resistant to depression-like behaviour, resembling the state produced by antidepressant treatment ^[3]. If losing the channel produces that phenotype, blocking it pharmacologically might do the same — and that inference is the entire premise of this line of work.

Spadin was the first peptide shown to do the blocking. The 2010 description reported that sortilin and TREK-1 interact physically, that the two colocalise in mouse cortical neurons, that spadin binds TREK-1 with an affinity near 10 nM, and that it blocks the channel in transfected cells, in cultured hippocampal neurons and in brain slices ^[3]. Its behavioural effects in mice appeared within four days rather than the several weeks typical of selective serotonin reuptake inhibitors, which is what made the approach interesting.

PE-22-28 is the engineering answer to spadin's short life in the body, not a different mechanism. The same channel, reached more potently and for longer ^[1].

One complication belongs here rather than in a footnote. In the stroke work, the peptide's action on TREK-1 was reported as biphasic — channel activity increased at low concentrations and was inhibited at higher ones, and the experimental design used that difference deliberately, applying a low amount to activate the channel during the ischaemic phase and a higher one later ^[2]. A molecule whose direction of effect depends on concentration is not adequately described as an inhibitor, and the simple label should be read with that in mind.

PE-22-28 Mechanism of Action

In vitro research

Channel pharmacology. In patch-clamp recordings from HEK cells expressing human TREK-1, PE-22-28 inhibited the channel with a reported half-maximal inhibitory concentration of 0.12 nM. The comparison figure reported for spadin under the same conditions is 40–60 nM, and the authors describe the shortened peptide as showing better specificity as well as better affinity ^[1].

Terminal modifications. The same study screened derivatives with altered N- and C-terminal ends. Some modifications maintained TREK-1 activity and others abolished it, in both cases without affecting the peptide's affinity for the channel — a dissociation between binding and functional block that is worth noting, since it means a derivative can occupy the target without doing what the parent molecule does ^[1].

Origin of the sequence. The heptapeptide was not chosen from a library. It was identified by studying what spadin degrades into in blood, which is why its sequence is a contiguous C-terminal fragment rather than an optimised design ^[1].

Synaptic markers in cultured neurons. In mouse cortical neurons, PE-22-28 and its derivatives were reported to raise expression of PSD-95, used in that work as a measure of synaptogenesis ^[1].

The target's upstream biology. Sortilin/NTSR3, the protein whose propeptide spadin comes from, interacts with TREK-1 and influences its expression at the membrane; that relationship has been reviewed by the originating group ^[5].

Findings in this section were obtained in transfected cell lines and cultured neurons. Nothing in them establishes anything about intact animals or about humans.

What Is PE-22-28 Being Researched For?

Two lines of preclinical work, both from the same laboratory:

• Depression, as a target-validation exercise for TREK-1 blockade — the behavioural screens used to characterise antidepressant candidates, together with measures of neurogenesis and synaptogenesis ^{[1, 4]}.
• Focal cerebral ischaemia and its mood sequelae — a mouse model combining an ischaemic insult with the behavioural tests, using the peptide's concentration-dependent biphasic action on the channel ^[2].

Neither line has advanced to a registered clinical trial. There is no human safety data, no pharmacokinetic study in humans, and no independent replication in the indexed literature of the central potency measurement. None of this research concerns research-grade material supplied for laboratory use.

Preclinical Research on PE-22-28

Animal research

Behavioural models and short-course administration

Design. Mice given PE-22-28 or its derivatives, assessed in the forced swimming test and, after four days of sub-chronic administration, in the novelty-suppressed feeding test ^[1].

Result as reported. Mice given the spadin analogues showed a significant reduction of immobility time in the forced swimming test. In the novelty-suppressed feeding test, PE-22-28 significantly reduced the latency to approach the food pellet. Neurogenesis was reported after only four days of administration, with the G/A-substituted derivative producing the most prominent effect, and PSD-95 expression rose in mouse cortical neurons ^[1].

Duration. The action of PE-22-28 and its analogues was reported to persist up to about 23 hours, against roughly 7 hours for spadin ^{[1, 4]}.

Limitations. The forced swimming test and the novelty-suppressed feeding test are screening assays selected for their sensitivity to existing antidepressants; they are not models of depression, and a compound that changes behaviour in them has demonstrated a property of the assay as much as of itself. All results come from the laboratory that designed the peptide, and the central comparison against spadin is internal to that laboratory.

Focal ischaemia and post-stroke mood behaviour

Design. A mouse model of focal ischaemia. A single low amount of mini-spadin, 0.03 µg/kg, was given intraperitoneally 30 minutes after the onset of ischaemia and once daily for seven days, with the stated intention of activating TREK-1 and producing neuroprotection. A higher amount, 3 µg/kg, was then given once daily on four days a week, with the stated intention of inhibiting the channel ^[2].

Result as reported. Electrophysiological study showed the biphasic action on TREK-1 described above. The peptide was reported to prevent loss of body mass and delayed dopaminergic degeneration in the substantia nigra, to improve ischaemia-induced motor and cognitive deficits, and to prevent the behavioural changes measured in the forced swimming and novelty-suppressed feeding tests. Increased neurogenesis and synaptogenesis were reported as contributing to those effects ^[2].

Limitations. A single study, from the same group, in one species, using a protocol whose two-phase design was built around the compound's own biphasic pharmacology — an arrangement that is mechanistically motivated and also difficult to control against. The paper itself is framed as first evidence, which is the correct weight to give it.

Findings described in this section were observed in mice. Nothing in them establishes anything about humans.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

PE-22-28 vs Related Compounds

Spadin, the parent

The 17-residue sortilin-propeptide fragment from which this peptide was derived, and the compound most of the TREK-1 literature is actually about ^{[3, 4]}. PE-22-28 is its C-terminal seven residues. Neither has entered clinical study.

Other shortened analogues

The 2017 paper describes a series, including derivatives with modified N- and C-terminal ends and a glycine-to-alanine substituted variant designated G/A-PE 22-28 that produced the most prominent neurogenesis result in that work ^[1]. These are distinct substances; a result attributed to one of them is not a result for the unmodified heptapeptide.

Fluoxetine and the small-molecule blockers

The originating group's own review notes that established antidepressants already in clinical use, fluoxetine among them, inhibit TREK-1 ^[4]. The channel is therefore not an untouched target; what is novel here is the peptide route to it.

Other neuropeptide research compounds

Semax, Selank and Cerebrolysin are also studied in central-nervous-system models, but they share no target, no mechanism and no research programme with this peptide. The grouping is by field, not by pharmacology.

No comparison of effect between these compounds is made on this page.

Chemical & Molecular Characteristics

PE-22-28 is an unmodified linear heptapeptide with free N- and C-termini: glycine, valine, serine, tryptophan, glycine, leucine, arginine. PubChem records molecular formula C35H55N11O9 and average mass 773.9 g/mol under compound identifier 165437303, with CAS registry number 1801959-12-5.

One tryptophan, which is both the analytical handle and a liability. The single indole is the only strong chromophore in the molecule and gives it usable absorbance at 280 nm — an advantage over the many short peptides in this field that have none. It is also the residue most vulnerable to oxidation and to photodegradation, and tryptophan oxidation products are numerous, close in mass, and not always resolved from the parent peak.

One arginine gives the molecule its charge. The C-terminal guanidinium is the only basic side chain, set against the C-terminal carboxylate and a free N-terminal amine. The peptide is therefore close to neutral in net charge at physiological pH, which is unusual for a short peptide and affects both its chromatographic behaviour and its solubility profile.

Two glycines make it conformationally loose. Glycine at positions 1 and 5 leaves the backbone unusually flexible for a peptide of this length. Whether that matters for target engagement is not addressed in the published work; what it does mean is that the molecule has no defined solution conformation to characterise.

Salt form matters for any mass figure. The PubChem record explicitly includes an acetate form, and material supplied as a reagent is commonly an acetate or trifluoroacetate salt. A mass measured on such material will not equal the free-peptide mass, and a purity figure that does not state the counter-ion and the water content is incomplete.

No UNII code resolves for this substance in the FDA/NCATS Global Substance Registration System, so that field is published as unknown rather than filled with a plausible value.

Frequently Asked Questions

Scientific References

1. Djillani A, Pietri M, Moreno S, et al.. Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity Frontiers in pharmacology; 2017. PMID 28955242 doi:10.3389/fphar.2017.00643
2. Pietri M, Djillani A, Mazella J, et al.. First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides Neuropharmacology; 2019. PMID 31325429 doi:10.1016/j.neuropharm.2019.107715
3. Mazella J, Pétrault O, Lucas G, et al.. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design PLoS biology; 2010. PMID 20405001 doi:10.1371/journal.pbio.1000355
4. Djillani A, Pietri M, Mazella J, et al.. Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin Pharmacology & therapeutics; 2019. PMID 30291907 doi:10.1016/j.pharmthera.2018.10.003
5. Mazella J, Borsotto M, Heurteaux C. The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1 Frontiers in pharmacology; 2018. PMID 30670975 doi:10.3389/fphar.2018.01541

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Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.