Compound reference
PE-22-28
Also known as PE 22-28, Spadin (22-28)
PE-22-28 is a synthetic heptapeptide and shortened spadin analog that blocks the TREK-1 potassium channel — a mechanistically novel, fast-acting antidepressant strategy validated in TREK-1-knockout mice. Its evidence, however, is entirely preclinical and from essentially one research group, with no human trials.
- CAS
- 1801959-12-5
- Formula
- C₃₅H₅₅N₁₁O₉
- Molar mass
- ≈773.9 g/mol
- Sequence
- Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR) — residues 22-28 of the sortilin propeptide
Research peptide; not an approved drug. Preclinical only, with no human trials.
Mode of action
PE-22-28 is a seven-residue peptide (Gly-Val-Ser-Trp-Gly-Leu-Arg) corresponding to residues 22–28 of the propeptide of sortilin (also called NTSR3). It is the shortest fragment of spadin — a natural sortilin-derived peptide — that retains the parent's key activity: blockade of TREK-1, a two-pore-domain ("leak") potassium channel expressed in the brain.
The rationale is clean target biology. TREK-1-knockout mice show a depression-resistant phenotype, which identifies TREK-1 as an antidepressant target; blocking the channel is expected to be mood-elevating, and to do so through a mechanism entirely different from the monoamine reuptake of conventional antidepressants. PE-22-28 is a potent and selective TREK-1 inhibitor (reported IC50 around 0.12 nM, roughly 300–500 times more potent than spadin), and in rodents this translates to antidepressant-like behavior with a notably fast onset and stimulation of hippocampal neurogenesis — the latter a process normally associated with the delayed action of SSRIs.
Main intended effect
A fast-acting antidepressant effect — with associated pro-neurogenic activity — achieved by blocking the TREK-1 potassium channel rather than by acting on monoamines.
Areas of interest
The driving interest is depression, specifically the prospect of a rapid-onset antidepressant (conventional antidepressants take weeks). Related interest covers hippocampal neurogenesis and neuroprotection. In the consumer market PE-22-28 is sold as a mood/antidepressant and nootropic research peptide.
Evidence for intended effects
The target and concept are well-supported. TREK-1's role is validated genetically (knockout mice), the founding spadin study established the antidepressant concept, and — importantly for human relevance — serum levels of the sortilin-derived propeptide family (which includes PE) are decreased in patients with major depressive disorder, consistent with the axis being involved in human depression. PE-22-28 itself is the optimized, more potent and more stable embodiment of that concept, with antidepressant-like activity in mouse models.
What is entirely missing is human efficacy. Every behavioral result is in rodents, the work comes essentially from a single research group, and there are no clinical trials of PE-22-28 in people. The human data point (decreased propeptides in depression) is a correlational biomarker finding, not a test of giving PE-22-28 to patients. So this is a promising, mechanistically distinctive candidate at an early, preclinical stage — not a demonstrated treatment.
| Strand | What exists | Tier |
|---|---|---|
| Target validation | TREK-1-knockout mice depression-resistant; spadin concept | Established (target) |
| PE-22-28 efficacy | Rodent antidepressant behavior; potent TREK-1 block | Preclinical (single group) |
| Human relevance | Sortilin propeptides decreased in MDD (correlational) | Biomarker only |
| Human efficacy | None | No trials |
Studied amounts (literature dosing context)
The antidepressant-like effects were demonstrated in mouse behavioral models with systemically administered peptide; the optimization work emphasized PE-22-28's improved in-vivo stability (duration of action extended to roughly 23 hours) over spadin. There is no established human dose. These are animal-study figures, and this page does not provide dosing guidance.
Safety and regulatory status
There is no human safety data for PE-22-28, because there have been no human studies of any kind. It is not an approved drug in any jurisdiction; it is sold as a research peptide for mood and cognition. As with other gray-market peptides, products labeled "PE-22-28" are of unverified identity and purity, and using an unstudied compound for self-treatment of a serious condition such as depression carries obvious, uncharacterized risk.
Sources
Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design
Foundational study (Mazella and colleagues, PLoS Biology 2010) introducing spadin — a natural peptide cleaved from the propeptide of sortilin (NTSR3) — as a blocker of the TREK-1 (TWIK-related) potassium channel, and proposing TREK-1 blockade as a new antidepressant strategy. Because TREK-1-knockout mice are resistant to depression, the authors reasoned that blocking the channel should be antidepressant; spadin produced antidepressant-like effects in rodent behavioral models with a faster onset than classical antidepressants and stimulated hippocampal neurogenesis. This paper established the target and the concept on which the shortened analog PE-22-28 was later built. All findings are in rodents.
Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity
Medicinal-chemistry and behavioral study (Djillani, Pietri, Moreno, Heurteaux and colleagues, Frontiers in Pharmacology 2017) that optimized spadin into shorter, more stable analogs and identified PE-22-28 (the seven-residue fragment, sequence GVSWGLR) as the lead. PE-22-28 inhibited TREK-1 with an IC50 of about 0.12 nM — roughly 300 to 500 times more potent than spadin — with improved in-vivo stability (duration of action extended from about 7 to 23 hours) and antidepressant-like activity in mouse behavioral models. This is the key paper defining PE-22-28 itself; all efficacy data are in rodents.
Serum sortilin-derived propeptides concentrations are decreased in major depressive disorder patients
Clinical observational study (Devader, Roulot, Moreno, Minelli and colleagues, Journal of Affective Disorders 2017) measuring serum concentrations of sortilin-derived propeptides — the endogenous family that includes spadin and the PE fragment — in patients with major depressive disorder versus healthy controls. The PE propeptide, which has potent antidepressant activity in rodents, was significantly decreased in depressed patients. The result supports the human relevance of the sortilin/TREK-1 antidepressant axis that PE-22-28 targets, but it is a correlational biomarker study, not a test of PE-22-28 efficacy in people.