Experimental antidepressant peptide (PE-22-28)
A synthetic peptide that blocks a brain ion channel linked to depression, producing rapid antidepressant effects in animal studies; experimental, not yet an approved drug.
- Class
- Synthetic neuroactive peptide (TREK-1 channel blocker, spadin analog)
- Status
- No approved therapeutic use; no published human clinical trial of any phase
- Best-supported effect
- Rapid antidepressant-like behavioral effects in rodent models (onset 1–4 days); in animal studies only
- Main caveat
- PE-22-28 has never been administered to humans in any published trial; human biomarker evidence validates the TREK-1/sortilin pathway but does not establish that this compound works in people
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
Snapshot
Class: Synthetic neuroactive peptide (TREK-1 channel blocker, spadin analog)
Evidence tier: Animal-only evidence
Status: No approved therapeutic use; no published human clinical trial of any phase
Best-supported effect: Rapid antidepressant-like behavioral effects in rodent models (onset 1–4 days); in animal studies only
Main caveat: PE-22-28 has never been administered to humans in any published trial; human biomarker evidence validates the TREK-1/sortilin pathway but does not establish that this compound works in people
What this is
PE-22-28 is a synthetic peptide analog of spadin, a fragment cleaved from the propeptide region of sortilin, a receptor protein involved in neurotrophin signaling. It was designed by researchers at the Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) in France as a shorter, metabolically more stable version of spadin with retained TREK-1 inhibitory activity. Its proposed mechanism — blocking the TREK-1 two-pore-domain potassium channel in mood-regulating brain regions — is supported by strong preclinical evidence from the originating research program. The notable translational context is that separate human biomarker studies have confirmed that sortilin-derived propeptide levels are altered in major depressive disorder and change after electroconvulsive therapy, lending biological plausibility to the TREK-1/sortilin pathway in human depression. However, biomarker validation of a pathway is not equivalent to clinical validation of a specific compound, and PE-22-28 itself has no published human trial record.
Evidence map
| Evidence layer | Grade | What it supports |
|---|---|---|
| Human | None for PE-22-28 | PE-22-28 has not been administered in any published human trial; separate biomarker studies confirm pathway relevance (sortilin-derived propeptide levels altered in MDD and after ECT) but do not establish PE-22-28 efficacy or safety in people |
| Animal | Moderate | Rapid antidepressant-like behavioral effects in rodent models (forced-swim, tail-suspension) within 1–4 days; enhanced synaptogenesis and neuroplasticity markers; neuroprotection and reduced post-stroke depressive behavior in stroke models; improved metabolic stability vs parent compound spadin |
| In vitro | Weak | Selective TREK-1 channel inhibition demonstrated in cellular electrophysiology; BDNF and synaptogenesis markers in cell culture models |
| Computational | None identified | No computational or docking data identified |
| Mechanism | Strong (preclinical) | TREK-1's role in depression well-established through knockout mouse phenotype, pharmacological channel blockade, downstream serotonergic and noradrenergic effects, BDNF upregulation, and hippocampal neurogenesis in rodent systems; human biomarker data independently corroborate pathway relevance |
> Replication caveat: The large majority of published preclinical PE-22-28 evidence originates from a single research program (Borsotto, Heurteaux, Lazdunski — IPMC, France). Independent replication in external laboratories is sparse and represents a key limitation of the current evidence base.
Claim check
| Claim | Verdict | Evidence layer | Confidence |
|---|---|---|---|
| Rapid antidepressant-like effects (faster onset than SSRIs) | Supported (animal) | Animal — rodent behavioral assays | Medium — single originating research group; limited independent replication |
| Human antidepressant efficacy | Not established | Human — biomarker studies only; no PE-22-28 administration trial | High — absence is clear and consistent across published research |
| Enhanced neuroplasticity and synaptogenesis | Supported (preclinical) | Animal / in vitro | Medium — preclinical models only; no human translation data |
| BDNF upregulation | Supported (preclinical) | Animal / in vitro | Medium — measured in animal and cell models; human relevance not established |
| Stroke recovery and post-stroke depression benefit | Supported (preclinical) | Animal — stroke rodent models | Medium — preclinical stroke models; no human stroke trial |
| TREK-1/sortilin pathway is relevant to human depression | Supported (observational biomarker) | Human — observational biomarker studies | Medium — observational associations; causality direction and therapeutic relevance of exogenous PE-22-28 not established |
| Safe substitute for or augment to prescribed antidepressants | Not established | None — no human safety or interaction data | High — absence of human safety and interaction data is clear |
Experimental exposure
This section reports exposure used in animal experiments only. It does not establish human dosing.
| Context | System | Experimental exposure | Duration | Endpoint | Limitation |
|---|---|---|---|---|---|
| Rodent antidepressant-effect studies | Mice and rats (depression behavioral models) | 100 µg/kg IV, IP, or SC (per per available sources preclinical range) | Acute single dose to short courses (1–14 days) | Forced-swim and tail-suspension behavioral scores; synaptogenesis markers | Rodent-to-human translation not established; all data from single IPMC research program |
| Rodent stroke model studies | Rats (ischemia/stroke models) | per available sources preclinical dose range; exact regimen not individually extracted | Days to weeks post-stroke | Neurological recovery scores; post-stroke depressive behavior | Rodent stroke model; no human stroke trial data |
Preclinical safety signals
| Signal | System | Notes |
|---|---|---|
| Cardiovascular safety of TREK-1 blockade | Not characterized in any published study | TREK-1 is expressed in cardiac tissue, vascular smooth muscle, and GI tract in addition to brain regions; long-term consequences of chronic exogenous TREK-1 blockade in cardiac electrophysiology, vascular tone, and arrhythmia are uncharacterized even in animal models |
| CNS safety and psychiatric risk profile | Not established | Fast-acting antidepressant mechanisms carry recognized risks in populations with bipolar disorder or psychosis; PE-22-28 has not been evaluated for these risks |
| Reproductive and developmental toxicology | Not established | No animal reproductive or developmental toxicology data extracted from source |
| Long-term neuroplastic effects of chronic dosing | Not characterized | Preclinical studies used short courses; cumulative effects of BDNF upregulation and neurogenesis stimulation over chronic dosing are not systematically described |
| Human adverse events | No data | PE-22-28 has not been administered to humans in any published study |
Regulatory status
| Region / body | Status | Notes |
|---|---|---|
| US (FDA) | Not approved | Not approved for any indication; not a controlled substance; not a recognized dietary supplement; source describes it as available only through research-chemical channels not authorized for human use |
| EU (EMA) | Not approved | Per available sources, no EMA approval; status not independently refreshed in this card |
| UK (MHRA) | Not approved | Per available sources, no MHRA approval; status not independently refreshed in this card |
| Canada (Health Canada) | Not approved | Per available sources, no Health Canada approval; status not independently refreshed in this card |
| WADA | Per available sources, S0 clause likely applies | PE-22-28 is not currently named on the WADA Prohibited List by name; Per available sources, WADA's S0 "non-approved substances" clause as arguably applicable because the compound is not approved for human therapeutic use anywhere; status not independently refreshed in this card against the current list |
No approved therapeutic status identified. This card describes a preclinical research peptide, not an approved medicine.
Mechanism
PE-22-28 selectively inhibits TREK-1 (TWIK-related K⁺ channel-1), a two-pore-domain potassium channel highly expressed in mood-regulating brain regions including the hippocampus and prefrontal cortex. The mechanistic rationale for antidepressant activity derives from TREK-1 knockout mouse studies showing that TREK-1-deficient mice are markedly resistant to depressive behavior across standard rodent assays — an effect associated with increased serotonergic and noradrenergic neurotransmission, enhanced BDNF expression, and hippocampal neurogenesis.
Pharmacologically, TREK-1 blockade by PE-22-28 is proposed to increase neuronal excitability in these circuits, drive downstream BDNF release, promote synaptogenesis, and produce a behavioral antidepressant phenotype in rodents faster than classical monoamine reuptake inhibitors. In stroke models, TREK-1 blockade is also associated with neuroprotective effects and reductions in post-ischemic depressive behavior.
PE-22-28 is an optimized analog of spadin, a naturally occurring TREK-1-blocking peptide derived from the sortilin propeptide. Its primary design advantage over spadin is improved metabolic stability and a longer effective window in animal experiments. The mechanism also involves modulation of the 5-HT₄ receptor and mGluR₂ receptor interactions in prefrontal serotonergic circuits, described in preclinical studies as a synergistic component of its antidepressant profile.
Mechanism limitation: All mechanistic characterization is from rodent or cellular systems. The degree to which these pathway interactions translate to human pharmacology is unknown. TREK-1 is also expressed outside the CNS — in cardiac tissue, vascular smooth muscle, and the GI tract — and the consequences of systemic TREK-1 blockade across these non-CNS tissues have not been characterized in any human or long-term animal safety context.
Chemistry
| Field | Value |
|---|---|
| Name | PE-22-28 |
| Aliases | Spadin analog, shortened spadin |
| Parent molecule | Spadin (sortilin propeptide fragment) |
| Type | Synthetic peptide; shortened and optimized analog of spadin |
| Sequence | Not individually extracted in the available literature for this card |
| Length | Source describes as a shortened analog of spadin (spadin is reported as 17 amino acids; PE-22-28 length not separately stated in source) |
| Topology | Linear |
| Modifications | Per available sources, improved metabolic stability compared to spadin; specific modification details not individually extracted |
| Molecular weight | Not extracted from source |
| CAS | Not present in source |
| Sequence confidence | Not extracted — source does not provide a full sequence string for PE-22-28 in this compiled bundle |
Open questions
- Human pharmacokinetics: Absorption, distribution, metabolism, and excretion of PE-22-28 have not been characterized in any species relevant to predicted human exposure. Without PK data, dose estimation for humans is speculative.
- Human efficacy trial: No Phase I, II, or III study has tested PE-22-28 in humans for safety, tolerability, dose-response, or antidepressant efficacy. Whether the rapid rodent behavioral effects translate to human benefit is entirely unknown.
- Cardiovascular safety of chronic TREK-1 blockade: TREK-1 is expressed in cardiac and vascular tissues. The consequences of sustained exogenous TREK-1 blockade for cardiac electrophysiology, arrhythmia risk, and vascular tone have not been characterized in chronic animal studies and have never been addressed in humans.
- Independent preclinical replication: The published PE-22-28 evidence base is concentrated in one originating French research program. External independent replication of the key preclinical findings is sparse, and assessment of the robustness and generalizability of the animal findings awaits broader corroboration.
- Pathway vs compound validation gap: Human biomarker studies confirm that sortilin-derived propeptide levels are altered in major depressive disorder — validating the TREK-1/sortilin pathway as biologically relevant. This does not validate PE-22-28 specifically: pharmacokinetics, off-target binding, dose-response, and human-disease-model translation remain untested for the compound itself.
- Long-term neuroplastic consequences: Preclinical studies used short dosing courses. The cumulative effects of BDNF upregulation, neurogenesis stimulation, and enhanced synaptogenesis over chronic or repeated PE-22-28 exposure are not characterized.
- Psychiatric safety profile: Fast-acting antidepressant mechanisms carry recognized risks in bipolar disorder and psychotic conditions (e.g., mania-switching with ketamine). PE-22-28 has not been evaluated for these risks.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could blocking TREK-1 in microglia (brain immune cells) reduce the inflammation seen in diseases like Alzheimer's?
If TREK-1 turns out to shape how microglia release inflammatory signals, a TREK-1 blocker like PE-22-28 could be worth testing in neurodegenerative conditions where depression and inflammation overlap. This is a reasonable hypothesis to test, not an established effect: the microglial TREK-1 role is proposed, not yet confirmed for this peptide.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8352055549621582 | openfold3-mlx |
| ranking score | 0.8918015360832214 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.450 | global PDE — lower = better |
| disorder | 0.103 | fraction disordered |
| chain pair ipTM (A, B) | 0.835 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | — |
| hardware | — |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | — |
| diffusion samples | 1 |
| runtime | 79s |
| predicted by | mlx@peptide |
| predicted at | 2026-05-03 |
▸citationbibtex
@peptide{pep10948,
sequence = {SPVWKTATC},
target = {kcnk2},
author = {peptidemodel},
year = {2026},
status = {computed}
}