# PE-22-28

> PE-22-28 is a synthetic seven-amino-acid peptide (Gly-Val-Ser-Trp-Gly-Leu-Arg) derived from spadin, a fragment of the sortilin propeptide. It was designed as a shortened spadin analog that blocks the TREK-1 potassium channel. In cell and mouse studies it showed higher TREK-1 affinity than spadin and antidepressant-like behavioral effects. It has not been tested in published human trials.

Canonical: https://peptideproperties.com/compounds/pe-22-28/

## Identity

- **Class:** Neuropeptides & Nootropic Research Compounds
- **Also known as:** Spadin analog
- **Molecular formula:** C35H55N11O9
- **Molecular weight:** 773.9 g/mol
- **Monoisotopic mass:** 773.4184 Da
- **CAS number:** 1801959-12-5
- **PubChem CID:** 165437303
- **InChIKey:** CMNBQRXBBJQIOA-YIHYGEMESA-N
- **Sequence:** GVSWGLR
- **Sequence notes:** Unmodified linear peptide with a free N-terminal amine and a free C-terminal carboxylic acid, as registered in PubChem; all residues L-configured

## Key facts

- Class: synthetic linear heptapeptide; shortened analog of the sortilin-derived peptide spadin
- Sequence: Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR), residues 22-28 of the sortilin propeptide
- Formula C35H55N11O9; molecular weight 773.9 g/mol (PubChem CID 165437303)
- CAS number 1801959-12-5
- Primary target studied: TREK-1 (TWIK-related potassium channel-1)
- Evidence base: in-vitro and mouse studies only; no published human trials
- Regulatory status: not approved by the FDA for any use

## What Is PE-22-28?

PE-22-28 is a seven-residue peptide designed by shortening spadin, a naturally derived peptide that blocks the TREK-1 potassium channel. Its name refers to its position: residues 22 to 28 of the sortilin propeptide, known as PE. Spadin itself corresponds to PE 12-28.[1]Researchers developed PE-22-28 to address a practical limitation of spadin. In mice, spadin's activity disappeared beyond about 7 hours after administration, so the team screened analogs and derivatives to improve stability and bioavailability. PE-22-28 was designed from the products of spadin breakdown in blood.[1]The interest in TREK-1 stems from the search for antidepressant targets beyond monoamine balance. A 2019 review notes that existing antidepressants are nonspecific and can cause serious adverse effects, and that fluoxetine is itself among the TREK-1 inhibitors with clinical efficacy in depression.[2]Most published work on PE-22-28 comes from a single French research program studying TREK-1 as a target in depression. The available evidence consists of patch-clamp experiments in cultured cells and behavioral and neurogenesis studies in mice.[1][2]

## Chemical Structure and Molecular Identity

PE-22-28 is a linear heptapeptide with the sequence Gly-Val-Ser-Trp-Gly-Leu-Arg. PubChem lists it under CID 165437303 with the molecular formula C35H55N11O9, a molecular weight of 773.9 g/mol and CAS number 1801959-12-5.The registered structure has a free amine at the N-terminal glycine and a free carboxylic acid at the C-terminal arginine, with all chiral residues in the L configuration. It contains one aromatic residue (tryptophan), one basic residue (arginine) and one hydroxyl-bearing residue (serine). PubChem's computed XLogP of -3.7 indicates a highly polar, water-favoring molecule. The single tryptophan residue absorbs ultraviolet light near 280 nm, a property commonly used to detect peptides during HPLC analysis.Because spadin spans PE 12-28, PE-22-28 corresponds to the last seven residues of spadin.[1] The original study also tested versions with altered N- or C-terminal ends. Some of these modifications kept TREK-1 blocking activity and others abolished it, while affinity for the channel was not affected.[1] One derivative, labeled G/A-PE 22-28, showed the most prominent effect on neurogenesis in that work.[1]

## Research History and Development

PE-22-28 emerged from a stepwise effort to turn spadin into a more stable and more potent TREK-1 blocker. The underlying biology begins with sortilin, also called neurotensin receptor-3, which is made as a precursor and cleaved by the enzyme furin in late Golgi compartments. That cleavage releases a 44-amino-acid propeptide, PE.[3]Spadin, a 17-amino-acid peptide derived from this propeptide, was reported to have antidepressant-like properties in rodents and to block TREK-1.[2][4] A review of the program notes that spadin acted within 4 days of treatment in animal models, compared with the 3 to 4 weeks typically needed for fluoxetine, but that its in vivo stability lasted no more than about 7 hours.[2]The group pursued several optimization strategies, including retro-inverso peptides, cyclization and shortening of the sequence.[2] Two retro-inverso spadin analogs retained antidepressant-like activity in mice, increased hippocampal neurogenesis after a 4-day treatment and, like spadin, showed no effects on pain, epilepsy or cardiac measures in that study.[4] Shortening produced PE-22-28, which a 2017 study characterized for TREK-1 affinity, behavioral activity and effects on neurogenesis and synaptogenesis.[1] A 2019 review summarized that shortened spadin analogs showed greater TREK-1 inhibition, improved antidepressant-like activity and prolonged in vivo bioavailability compared with spadin.[2]

## Mechanisms Studied in Research

The main mechanism studied for PE-22-28 is blockade of TREK-1, a two-pore-domain potassium channel that this research group has proposed as a target in depression. Sortilin physically interacts with TREK-1, and both the sortilin propeptide and spadin block TREK-1 activation.[3]In patch-clamp recordings on human embryonic kidney (HEK) cells expressing human TREK-1, PE-22-28 showed greater specificity and affinity for the channel than spadin. The study reported an IC50 of 0.12 nM for PE-22-28, compared with 40 to 60 nM for spadin.[1]Downstream of TREK-1, the studied effects center on brain plasticity. In mouse experiments, PE-22-28 and its derivatives induced neurogenesis after a 4-day treatment, and in cultured mouse cortical neurons they increased expression of PSD-95, a marker used to measure synaptogenesis.[1]A related short analog that the same group calls mini-spadin showed a biphasic action on TREK-1 in electrophysiology studies: lower concentrations increased channel activity, while higher concentrations inhibited it.[5] The abstracts describe mini-spadin as a short spadin analog without stating its sequence, so these findings are reported separately here.

## Key Findings From Published Studies

Published findings on PE-22-28 come from cell-based assays and mouse behavioral models; there are no human efficacy data. The key results are summarized below by model.
- Cell model (hTREK-1/HEK cells): PE-22-28 blocked TREK-1 with an IC50 of 0.12 nM, a higher affinity than spadin.[1]
- Mouse forced swimming test: mice treated with PE-22-28 and related analogs showed a significant reduction in immobility time, a standard readout in antidepressant screening.[1]
- Mouse novelty suppressed feeding test: after a 4-day sub-chronic treatment, PE-22-28 significantly reduced the latency to eat.[1]
- Neurogenesis and synaptogenesis: PE-22-28 and its analogs induced neurogenesis after 4 days of treatment and increased PSD-95 expression in cultured cortical neurons.[1]Two further mouse and cell studies used mini-spadin. In a mouse model of focal cerebral ischemia and post-stroke depression, mini-spadin prevented body weight loss and delayed dopaminergic degeneration in the substantia nigra, improved motor and cognitive deficits, and prevented depression-like behavior in the forced swim and novelty suppressed feeding tests.[5] In pancreatic beta-cell experiments, the sortilin propeptide, spadin and mini-spadin protected cells against interleukin-1β-induced death through calcium-dependent CaM-kinase signaling and CREB activation, and mini-spadin promoted beta-cell proliferation.[6]
### Evidence at a glance
ModelMolecule testedMain readouthTREK-1/HEK cellsPE-22-28TREK-1 block, IC50 0.12 nMMouse behavioral testsPE-22-28 and derivativesReduced immobility; shorter eating latencyMouse brain and cortical neuronsPE-22-28 and derivativesNeurogenesis; increased PSD-95Mouse stroke modelMini-spadinMotor, cognitive and depression-like outcomesPancreatic beta cellsMini-spadin, spadin, PESurvival and proliferationThese results come from a small number of studies by one research network, and independent replication has not yet been reported in the indexed literature.With a short synthetic heptapeptide, researchers typically confirm sequence identity and purity through HPLC and mass-spectrometry certificates of analysis.

## Regulatory and Research Status

PE-22-28 is an investigational research peptide that has not been approved by the US Food and Drug Administration or, to our knowledge, any other regulator. No human clinical trials of PE-22-28 appeared in the PubMed records reviewed for this page.Human data in this research area relate to the parent molecules rather than to PE-22-28. A review describes the detection of soluble sortilin and the sortilin propeptide in human serum, with levels affected in patients with major depressive disorder, and discusses them as potential biomarkers.[3]The current evidence base for PE-22-28 is limited to in-vitro and rodent work. Its pharmacokinetics, safety and activity in humans have not been characterized in peer-reviewed studies, and the abstracts reviewed here do not report toxicology data for the heptapeptide itself.

## FAQ

**What is PE-22-28?**
PE-22-28 is a synthetic seven-amino-acid peptide, Gly-Val-Ser-Trp-Gly-Leu-Arg, corresponding to residues 22 to 28 of the sortilin propeptide. Researchers designed it as a shortened version of spadin to block the TREK-1 potassium channel with greater stability. It has been studied in cultured cells and mice, where it showed antidepressant-like effects in behavioral tests, but it has not been evaluated in published human trials.

**Is PE-22-28 the same as spadin?**
No. Spadin is a 17-amino-acid peptide corresponding to residues 12 to 28 of the sortilin propeptide, while PE-22-28 contains only the final seven residues of that sequence. In patch-clamp studies on cells expressing human TREK-1, PE-22-28 showed an IC50 of 0.12 nM, compared with 40 to 60 nM reported for spadin, indicating higher affinity for the channel.

**What is the molecular weight of PE-22-28?**
PubChem lists PE-22-28 (CID 165437303) with a molecular weight of 773.9 g/mol and the molecular formula C35H55N11O9. Its CAS number is 1801959-12-5. The registered structure is an unmodified linear heptapeptide with a free N-terminal amine and a free C-terminal acid. Salt forms such as the acetate have a different overall mass.

**How does PE-22-28 work?**
Research describes PE-22-28 as a blocker of TREK-1, a two-pore-domain potassium channel. In mouse studies, PE-22-28 reduced immobility in the forced swimming test, shortened eating latency in the novelty suppressed feeding test, induced neurogenesis after 4 days of treatment and increased the synaptic marker PSD-95 in cultured cortical neurons. Its mechanism has not been studied in humans.

**Is PE-22-28 FDA approved?**
No. PE-22-28 is not approved by the US Food and Drug Administration for any use, and no human clinical trials of it appeared in PubMed as of October 2026. It is an investigational research peptide whose published evidence is limited to cell-based experiments and rodent models from a small number of laboratories.

**What does the research on PE-22-28 show?**
A 2017 study reported that PE-22-28 blocked TREK-1 more potently than spadin in cells and produced antidepressant-like effects in mouse behavioral models, along with increased neurogenesis and synaptogenesis. A 2019 review concluded that shortened spadin analogs showed greater TREK-1 inhibition and longer in vivo bioavailability than spadin. All of this evidence is preclinical.

## 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
2. 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
3. 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
4. Veyssiere J, Moha Ou Maati H, Mazella J, et al. Retroinverso analogs of spadin display increased antidepressant effects. Psychopharmacology 2015. PMID: 25080852
5. 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
6. Daziano G, Blondeau N, Béraud-Dufour S, et al. Sortilin-derived peptides promote pancreatic beta-cell survival through CREB signaling pathway. Pharmacological research 2021. PMID: 33737242