PE 22-28
PE22-28, mini-spadin, shortened spadin analogue, sortilin propeptide 22-28, GVSWGLR
PE 22-28 is a seven-residue fragment of the propeptide cleaved from sortilin during its maturation. It is the shortened, more potent descendant of spadin (PE 12-28), a peptide developed at the CNRS Institute of Molecular and Cellular Pharmacology near Nice as a fast-acting antidepressant that blocks the TREK-1 potassium channel. Its mechanism is unusually well characterised for a compound in this class. It has never been tested in a human.
Mechanism
The starting point is genuinely elegant. Sortilin is synthesised with an N-terminal propeptide that is cleaved by furin during maturation, and the freed propeptide is not simply waste. It interacts with the two-pore-domain potassium channel TREK-1. TREK-1 is a background leak channel whose activity hyperpolarises serotonergic neurons and dampens their firing. Mice lacking TREK-1 show a depression-resistant phenotype, which made the channel an attractive antidepressant target. Spadin, corresponding to residues 12 to 28 of the sortilin propeptide, was designed to block TREK-1 and produced antidepressant-like effects in mice within four days rather than the several weeks required by SSRIs, without the side effects associated with TREK-1 loss elsewhere.
PE 22-28 is the minimal active core, residues 22 to 28 (Gly-Val-Ser-Trp-Gly-Leu-Arg), designed from the study of spadin's blood degradation products. Truncation improved matters substantially: in patch-clamp recordings from hTREK-1-expressing HEK cells it inhibited the channel with an IC50 of about 0.12 nanomolar against 40 to 60 nanomolar for spadin, and its duration of action in vivo extended to roughly 23 hours from spadin's seven. Blocking TREK-1 removes the hyperpolarising brake on dorsal raphe serotonergic neurons, increasing their firing rate, and downstream effects include increased hippocampal neurogenesis and synaptogenesis with raised PSD-95 expression. Later work described a biphasic action on TREK-1 (channel activation at low doses and inhibition at higher ones), which complicates the simple blocker model and matters for anyone assuming that more is better.
What the research shows
The mechanistic literature is strong by the standards of this class. Spadin's identification in PLoS Biology in 2010 was followed by demonstrations of antidepressant-like activity without TREK-1-related side effects, regulation of synaptogenesis in vitro and in vivo, and a body of work on sortilin's role in controlling TREK-1 surface expression. PE 22-28 itself was characterised in 2017 as the shortened analogue with better TREK-1 affinity, better in vivo stability and antidepressant activity in the forced swimming and novelty-suppressed feeding tests, with neurogenesis after only four days of treatment. A 2019 study reported that mini-spadin protected against stroke damage and post-stroke depression in mice, preventing weight loss and delayed dopaminergic degeneration in the substantia nigra while improving motor and cognitive deficits, with enhanced neurogenesis and synaptogenesis; that study used a low intraperitoneal dose of 0.03 micrograms per kilogram to activate TREK-1 in the neuroprotective phase and a higher dose of 3 micrograms per kilogram to inhibit it for the antidepressant phase.
What has not happened is any human study. There is no Phase 1 trial, no registered study, no published human exposure. The antidepressant claim rests entirely on rodent behavioural despair paradigms (forced swim, tail suspension, chronic mild stress), which have a notoriously poor record of predicting antidepressant efficacy in people. Numerous compounds have produced clean, rapid, robust effects in these models and failed in clinical trials. The four-day onset that makes PE 22-28 interesting is a mouse phenomenon. It has never been observed in a person, because no person has been studied. It is also worth noting how narrow the literature is: a PubMed search for the exact term "PE 22-28" returns a single paper. The rest of the evidence base concerns spadin.
Evidence assessment
Preclinical only
Well-characterised target engagement at TREK-1 and consistent rodent antidepressant-like activity, but no human study of any kind has been conducted, and rodent behavioural despair models predict human antidepressant efficacy poorly.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity Preclinical only
PE 22-28 inhibited TREK-1 with an IC50 of 0.12 nM (versus 40-60 nM for spadin), reduced immobility in the forced swimming test and latency to feed after four days of sub-chronic treatment, induced neurogenesis after four days, increased PSD-95 expression in cortical neurons, and extended duration of action to about 23 hours from spadin's 7.
Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design Preclinical only
Established the sortilin propeptide as a TREK-1 blocker with rapid antidepressant-like activity in mice, founding the research programme that produced PE 22-28.
First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides Preclinical only
Mini-spadin prevented weight loss and delayed dopaminergic degeneration in substantia nigra, improved motor and cognitive deficits and prevented depressive-like behaviour, with enhanced neurogenesis and synaptogenesis; electrophysiology showed a biphasic action on TREK-1, activation at low doses and inhibition at higher ones.
Spadin as a new antidepressant: absence of TREK-1-related side effects Preclinical only
Spadin produced antidepressant-like effects without the side effects predicted from TREK-1 inhibition.
In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin Preclinical only
Spadin increased synaptogenesis markers both in culture and in vivo, providing a structural correlate for the behavioural effects.
Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin Preclinical only
Summarises the spadin and PE 22-28 programme and the case for TREK-1 as a rapid-onset antidepressant target, while noting the absence of clinical translation.
The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1 Preclinical only
Describes how sortilin regulates TREK-1 surface expression and how its propeptide gives rise to the spadin family.
Safety
No human safety data exists. The rodent literature emphasises the absence of TREK-1-related side effects, which addresses a specific anticipated liability rather than establishing general safety. Two considerations deserve stating. TREK-1 is expressed well beyond serotonergic neurons (in cardiac tissue, smooth muscle, astrocytes and pancreatic beta cells), so systemic blockade is not a neurologically confined intervention. And the reported biphasic action on TREK-1, with activation at low concentrations and inhibition at higher ones, means the dose-response relationship is not monotonic; a mistaken assumption that more produces more could produce the opposite effect on the target. No toxicology package is in the public domain, and material sold to consumers is synthetic peptide of unverified purity made outside pharmaceutical GMP.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation. Not a controlled drug, but as an unlicensed medicinal product it may not lawfully be sold, supplied or advertised for human use under the Human Medicines Regulations 2012. |
| United States | Not FDA-approved for any indication and never studied in a registered human trial. It is sold in the US only as an unapproved substance under a "research use only" label. |
| WADA (sport) | Not named on the WADA Prohibited List. As a non-approved pharmacological substance it would fall within the scope of category S0. |
Questions
PE 22-28 is the minimal active core of spadin: the last seven residues, Gly-Val-Ser-Trp-Gly-Leu-Arg, of the 17-residue parent PE 12-28. Truncation improved TREK-1 affinity roughly 300- to 500-fold (IC50 about 0.12 nM versus 40-60 nM) and extended the in vivo duration of action from around 7 hours to around 23.
No. There is no Phase 1 trial, no registered study and no published human exposure. The antidepressant evidence is entirely rodent behavioural work in forced swim, novelty-suppressed feeding and chronic mild stress paradigms, which have a poor track record of predicting clinical antidepressant efficacy.
Not necessarily, and this is an unusual and important point. A 2019 study reported a biphasic action on TREK-1: activation of the channel at low doses and inhibition at higher ones. Since the antidepressant hypothesis depends on inhibition, the dose-response relationship is not monotonic and assumptions about escalation are unsafe.
Less than it appears. A PubMed search for the exact term returns one paper, the 2017 characterisation. The 2019 stroke study used mini-spadin. Everything else in the literature concerns the parent compound spadin, and applies to PE 22-28 only by inference.
No. TREK-1 is expressed in cardiac tissue, smooth muscle, astrocytes and pancreatic beta cells. Systemic administration is not a neurologically confined intervention, and the peripheral consequences have not been characterised in humans.