PE-22-28 Research: What Published Studies Have Investigated

What is PE-22-28?

What is PE-22-28? It is a seven-amino-acid peptide, described by Djillani and colleagues in Frontiers in Pharmacology in 2017 (PMID 28955242). Its name follows the convention used for its parent: the numbers denote residues 22 to 28 of the propeptide from which the family is derived. Its parent is spadin, designated PE 12-28 — a seventeen-residue peptide corresponding to residues 12 to 28 of the same propeptide.

That propeptide is itself a by-product. When sortilin — also known as neurotensin receptor 3, or NTSR3 — is matured, a propeptide is cleaved off and secreted. Mazella and colleagues reported in PLoS Biology in 2010 (PMID 20405001) that a fragment of this discarded piece acts on the TREK-1 potassium channel, and named it spadin. PE-22-28 is a further-shortened version of that fragment.

One naming caution, because it costs nothing to state: the target here is TREK-1, a potassium channel, and the compound is a channel blocker. This is a different kind of pharmacology from the receptor-agonist story that most peptides in this catalogue tell, and figures quoted for it (IC50 values from patch-clamp recordings) are not comparable to receptor binding constants quoted elsewhere.

Discovery and origin in the literature

A knockout mouse came first

The programme begins with genetics, not chemistry. Heurteaux and colleagues reported in Nature Neuroscience in 2006 (PMID 16906152) that deleting the background potassium channel TREK-1 in mice produced what they described as a depression-resistant phenotype in the behavioural assays conventional in that field. If removing a channel produces that phenotype, then blocking the channel pharmacologically becomes an obvious question — and that is the question the rest of this literature asks.

Spadin, and then spadin’s breakdown products

Mazella and colleagues (2010) reported that sortilin/NTSR3 interacts with TREK-1, that the two co-localise in mouse cortical neurons, and that spadin binds specifically to TREK-1 with an affinity of 10 nM and blocks the channel in several neuronal preparations. They also reported behavioural results in mice across several assays used as antidepressant screens, and an increase in hippocampal CREB phosphorylation and neurogenesis after a four-day treatment.

The limitation that produced PE-22-28 is stated in the 2017 paper: spadin’s in-vivo activity disappeared beyond about seven hours after administration. Rather than redesigning from scratch, the group studied spadin’s blood degradation products — asking what the peptide turns into — and from that analysis designed the seven-residue PE 22-28. It is an unusually direct piece of medicinal-chemistry reasoning, and it is the most genuinely interesting thing about the molecule.

Reference data

The record here is thinner than for most compounds in this library, and the table reflects that honestly. No molecular formula, molecular weight or CAS number is listed because we could not source one: a PubChem lookup by name returns no compound entry, and none of the primary papers we checked states a registry number. Guessing any of those fields would be worse than leaving them blank.

For context, the parent peptide does have a chemical record: spadin is catalogued in PubChem, which is a useful reminder that absence of an entry for PE-22-28 reflects how new and how narrow this compound is rather than anything about its parent. No reconstitution procedure, quantity or route is given or implied on this page.

Mechanisms researchers have examined

• TREK-1 channel inhibition — the central and essentially only mechanism. Djillani et al. (2017) reported patch-clamp measurements on human TREK-1 expressed in HEK cells giving an IC50 of 0.12 nM for PE 22-28 against 40–60 nM for spadin, describing better specificity and affinity for the channel.
• Structure–activity at the peptide termini — the same paper reported that different modifications of the N- or C-terminal ends maintained or abolished channel activity without affecting binding affinity, separating the two properties experimentally.
• Sortilin/NTSR3 as the upstream source — Mazella and colleagues (2018, Front Pharmacol, PMID 30670975) review sortilin’s role as the progenitor of spadin and its involvement in the membrane expression of TREK-1, placing the peptide in a wider trafficking story.
• Downstream cellular readouts — the 2017 paper reported increased PSD-95 expression in mouse cortical neurons and neurogenesis after a four-day treatment, with the G/A-substituted analogue prominent among the derivatives tested.

Each point names what was measured in a defined system, not an effect in a reader. Note also that the potency figures above are functional inhibition constants from a heterologous expression system; they describe the molecule’s behaviour at a channel in a dish.

Research areas in the literature

There are two, and they are close together. The first is rodent behavioural pharmacology: the 2017 paper reported reduced immobility in the forced swimming test and, after four days of sub-chronic administration, reduced latency to eat in the novelty-suppressed feeding test. These are the standard rodent screens of that field, and they are screens — assays selected historically because known antidepressants score on them, not measures of a mood state in an animal.

The second is stroke. Pietri and colleagues (2019, Neuropharmacology, PMID 31325429) reported what they described as first evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides. Beyond those, the record consists of review articles: Borsotto and colleagues (2015, Br J Pharmacol, PMID 25263033) on TREK-1 and TASK-3 as depression targets, and Djillani and colleagues (2019, Pharmacol Ther, PMID 30291907) surveying TREK-1 blockers with a focus on spadin.

Research models and evidence status

The literature is one laboratory

This is the most important thing to know about PE-22-28 and it belongs stated plainly rather than implied. Mazella, Borsotto, Heurteaux, Djillani and Pietri are the recurring author set across essentially every paper cited on this page, working at the same French institute. That is not a criticism — new molecules almost always start this way, and a group that discovers a target is naturally the group that characterises it. But a body of work in which the discovering laboratory has produced the primary papers and the reviews has not yet been tested by the thing that actually validates findings, which is somebody else reproducing them.

What is not established

There are no registered clinical trials of PE-22-28; a ClinicalTrials.gov search returns none. There is no independent replication of the sub-nanomolar potency figure that we could locate. The behavioural results are rodent screening assays, and the widely acknowledged translational failure rate of those assays in psychiatric drug development is itself a well-known problem in the field. The compound has no chemical registry entry, which is a practical obstacle to independent verification of identity. And there is no published human pharmacokinetic, safety or tolerability data of any kind.

Nothing in this literature establishes any property of the supplied research material in a person. This page makes no efficacy, therapeutic, antidepressant, neurogenic or other use claim of any kind, and the material is supplied for laboratory research use only — not for human or veterinary use.

Why this page is short

Because the evidence is. A longer page here would be padding, and padding a thin literature is how a compound’s reputation gets ahead of its data. The material above is what is actually published; when more appears, this page will grow.

How to verify this compound yourself

The absence of a chemical registry entry makes the certificate of analysis unusually load-bearing for this compound rather than less so:

• Mass-spec identity — with no CAS number and no PubChem record to cross-check against, the mass spectrum is the primary independent evidence that the vial contains a seven-residue peptide of the expected composition rather than a different fragment of the same parent. Any supplier’s stated sequence should be checked against the measured mass.
• HPLC purity — a seven-residue synthesis is short and comparatively clean, which means the purity figure should be high and an unremarkable one is a reasonable expectation rather than an achievement.
• Which peptide, exactly — the family contains at least three closely related species (the propeptide, spadin/PE 12-28, and PE 22-28), plus the terminal-modified derivatives described in the 2017 paper. These differ substantially in mass and are trivially distinguished by mass spectrometry, but not by appearance or by a label.
• Counter-ion documentation — as with any synthetic peptide, usually trifluoroacetate; a documentation question affecting net peptide content per unit mass.

See how to read a COA for what each certificate line means, and how to verify peptide purity for how the methods fit together. The exact batch received can be checked on the self-serve verify tool.

Research-grade sourcing and verification

PE-22-28 is not held in stock. It is listed on our sourcing catalogue as available to order — our supplier lists it, we have not bought it, and material of this kind typically takes about two to three weeks to reach us. For laboratory research use only, it is supplied with a per-batch Certificate of Analysis reporting HPLC purity (%) and mass-spec identity confirmation, verifiable at the lot level. For an adjacent compound in this library whose literature is similarly narrow and whose page says so, see Pinealon research; for another CNS-directed research peptide with a broader but still largely regional literature, see Selank research. This is sourcing and quality-assurance framing only.

Frequently asked questions

Literature cited

1. Heurteaux C, Lucas G, Guy N, et al. “Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype.” Nat Neurosci. 2006;9(9):1134–1141. PMID 16906152. pubmed.ncbi.nlm.nih.gov/16906152.
2. 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 Biol. 2010;8(4):e1000355. PMID 20405001. pubmed.ncbi.nlm.nih.gov/20405001.
3. Borsotto M, Veyssiere J, Moha Ou Maati H, et al. “Targeting two-pore domain K+ channels TREK-1 and TASK-3 for the treatment of depression: a new therapeutic concept.” Br J Pharmacol. 2015;172(3):771–784. PMID 25263033. pubmed.ncbi.nlm.nih.gov/25263033.
4. Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M. “Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity.” Front Pharmacol. 2017;8:643. PMID 28955242. pubmed.ncbi.nlm.nih.gov/28955242. The paper that introduces PE 22-28.
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.” Front Pharmacol. 2018;9:1541. PMID 30670975. pubmed.ncbi.nlm.nih.gov/30670975.
6. Djillani A, Pietri M, Mazella J, Heurteaux C, Borsotto M. “Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin.” Pharmacol Ther. 2019;194:185–198. PMID 30291907. pubmed.ncbi.nlm.nih.gov/30291907.
7. Pietri M, Djillani A, Mazella J, Borsotto M, Heurteaux C. “First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides.” Neuropharmacology. 2019;158:107715. PMID 31325429. pubmed.ncbi.nlm.nih.gov/31325429.