PE-22-28

A short spadin-derived heptapeptide that selectively blocks the TREK-1 potassium channel, studied in rodent models as a fast-acting antidepressant candidate with pro-neurogenic effects.

What it is

PE-22-28 is a synthetic 7-residue peptide with the sequence Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR). It corresponds to residues 22 to 28 of spadin, an endogenous peptide released during the maturation of the sortilin receptor propeptide. Spadin was first described by Mazella and colleagues in a 2010 PLoS Biology paper as a natural blocker of the TREK-1 background potassium channel that produced antidepressant-like activity in mice.

The parent spadin peptide had a short duration of action and modest potency, which limited its usefulness as a research tool. To address this, Djillani, Borsotto, Mazella and co-workers synthesised a library of shortened spadin fragments and screened them for TREK-1 affinity, plasma stability and behavioural activity. PE-22-28 emerged as the lead fragment from that 2017 work, combining much higher channel affinity with markedly longer in vivo persistence. It belongs to the class of spadin-analogue neuroactive research peptides.

How it works

TREK-1 (encoded by the KCNK2 gene) is a two-pore-domain background potassium channel that helps set the resting membrane potential of neurons. In the framework proposed by the Mazella group, elevated TREK-1 activity in mood-related circuits, including the hippocampus and prefrontal cortex, is associated with a depressive-like state, and blocking the channel produces a rapid antidepressant-like response. TREK-1 knockout mice are resistant to depression-like behaviour, which is the genetic evidence underpinning this target.

PE-22-28 acts as a selective inhibitor of TREK-1. By reducing the outward potassium leak the channel provides, it depolarises target neurons and is proposed to enhance serotonergic signalling and downstream hippocampal neurogenesis. Because the mechanism does not depend on monoamine reuptake blockade, interest in the peptide centres on the possibility of a faster onset than classical antidepressants in preclinical models. All of the supporting evidence to date is preclinical and derived from rodents.

What the research shows

The defining dataset comes from Djillani et al. (2017) in Frontiers in Pharmacology. In that study PE-22-28 inhibited TREK-1 with an IC50 near 0.12 nM, roughly a 300-fold improvement over spadin, which sits around 40 to 60 nM. In binding-normalised electrophysiology it produced about 55% channel inhibition at 100 nM. In the acute forced swim test, a single low-microgram-per-kilogram dose cut immobility time from about 161.7 s in saline controls to about 91.8 s. A four-day sub-chronic course increased hippocampal BrdU-positive cell counts, a marker of new neuron formation, and reduced latency to feed in the novelty-suppressed feeding paradigm. The analogue also persisted far longer in vivo than spadin, with reported half-time effects out to roughly 23 hours versus about 6 to 7 hours for the parent peptide.

Side Effects

PE-22-28 is a synthetic seven-residue peptide derived from spadin, and every safety observation to date comes from cell and rodent studies. No human clinical trials have been conducted, so there is no human side-effect profile, no established safe exposure, and no adverse-event data in people. What follows summarizes what the preclinical literature reports and what remains theoretical based on the biology of its target, the TREK-1 (KCNK2) potassium channel. None of it should be read as evidence of safety in humans.

The bottom line is that PE-22-28 has no established human side-effect profile. Rodent studies suggesting an absence of harm cannot substitute for human safety data, and the physiological roles of TREK-1 in pain, seizure control, cardiovascular function, and ischemic protection mean the consequences of blocking it in people remain genuinely unknown.

At a glance

The molecular formula is C₃₅H₅₅N₁₁O₉, sequence GVSWGLR, as listed on PubChem and vendor certificates of analysis.

Dosing

Every dose reported for PE-22-28 comes from preclinical rodent studies, almost all in male C57BL/6J mice. There is no established human dose, and PE-22-28 has not been tested in people. The figures below are the weight-based doses used by researchers in mouse behavioral experiments, not instructions for use, and they are reproduced here as educational summaries of the published literature.

No human dose for PE-22-28 exists, and no clinical trials have defined one. Converting these rodent milligram-per-kilogram and microgram-per-kilogram figures to a human dose is not scientifically validated, so the numbers above should be read only as documentation of how researchers dosed laboratory animals. PE-22-28 is offered for laboratory research use only.

Preparing it

PE-22-28 is supplied as a lyophilised powder and is reconstituted with bacteriostatic or sterile water before use in the lab. See the reconstitution guide for handling and mixing, and the concentration guide for working out volumes per vial. Store the sealed vial cold and keep reconstituted material at 2-8 C, protected from light.

Where to go next

Last updated on July 3, 2026