PE-22-28 is a seven-amino-acid peptide designed to block TREK-1, a potassium channel that helps hold neurons at their resting voltage. It is the shortened descendant of spadin, a peptide cut from the propeptide of the sorting receptor sortilin. In channel recordings and mouse models, the short version proved more potent and longer-lasting than the peptide it came from, which is why it is now a common tool for TREK-1 pharmacology.
The story of PE-22-28 runs from a protein-trafficking receptor to an ion channel to a set of rodent behavioral and neuroplasticity assays. The sections below follow that chain, then set out how thin the published record still is.
At a glance
- Class: Synthetic heptapeptide; spadin analog; TREK-1 (K2P2.1) channel inhibitor
- Origin: Designed by French researchers at the Institut de Pharmacologie Moléculaire et Cellulaire from spadin degradation products; reported in 2017
- Structure: Gly-Val-Ser-Trp-Gly-Leu-Arg; C35H55N11O9; MW 773.9 g/mol; CAS 1801959-12-5
- Main research areas: TREK-1 electrophysiology, peptide stability, rodent depression models, hippocampal neurogenesis, synaptic markers
- Regulatory status: Not approved by the FDA for any use; research reagent only
Structure and origin
Sortilin is a receptor that sorts proteins between the Golgi apparatus, endosomes and the cell surface. Like many receptors, it is made as a longer precursor, and during maturation an enzyme removes a short N-terminal propeptide (often written PE). That propeptide is released from cells rather than simply discarded. In 2010 the Valbonne group that studied it reported that a 17-residue fragment of the propeptide, residues 12 to 28, bound to and inhibited TREK-1. They named it spadin, and in mouse models it behaved like a candidate antidepressant (Borsotto et al., 2015).
Spadin had two practical problems: it was relatively large for a peptide drug candidate, and its activity in mice faded within hours. Djillani and colleagues looked at the fragments that appear when spadin is degraded in blood and found that a seven-residue segment corresponding to positions 22 to 28 of the propeptide kept the ability to block TREK-1. They named it PE 22-28 and also made a variant with alanine in place of the first glycine, called G/A-PE 22-28 (Djillani et al., 2017).
Mechanism: what the research shows
TREK-1, encoded by the KCNK2 gene, is a two-pore-domain (K2P) potassium channel. It produces a “leak” current that keeps neurons hyperpolarized, and its opening is tuned by membrane stretch, temperature, intracellular pH, polyunsaturated fatty acids and phosphorylation. Mice lacking TREK-1 behaved differently from wild-type mice in standard depression-model tests, which drew interest to TREK-1 blockers as research tools (Borsotto et al., 2015). The channel also takes part in sensing heat, mechanical and other painful stimuli in mice, so its function is not limited to mood-related circuits (Alloui et al., 2006).
In patch-clamp recordings from cells expressing TREK-1, PE 22-28 inhibited the channel at sub-nanomolar concentrations, compared with tens of nanomolar for spadin. The authors also tested selectivity against other K2P channels and the cardiac hERG channel. In mice, the time over which the shortened analogs remained active in behavioral tests was several-fold longer than for spadin (Djillani et al., 2017).
Key areas of study
Channel electrophysiology
The core use of PE-22-28 is as a TREK-1 inhibitor in whole-cell recordings. Its potency and small size make it a convenient comparator for spadin and for non-peptide TREK-1 modulators, and the selectivity panel in the original paper gives a starting point for interpreting off-target effects (Djillani et al., 2017).
Rodent depression models
The 2017 study used several standard mouse paradigms: the forced swim test, the novelty-suppressed feeding test, learned helplessness and a corticosterone-induced model. Each is a behavioral assay used to screen compounds for antidepressant-like activity in rodents. The shortened analogs were compared directly with spadin in these tests, and their activity was followed over time to estimate how long it lasted (Djillani et al., 2017). These are model readouts, not measures of mood.
Neurogenesis and synaptic markers
Spadin was earlier linked to synaptogenesis in cultured neurons and in mice, with changes in synaptic protein markers (Devader et al., 2015). Djillani and colleagues extended this to the analogs, measuring BrdU-labeled new cells in the hippocampus after a few days of treatment and PSD-95, a postsynaptic marker, in cultured mouse cortical neurons (Djillani et al., 2017).
TREK-1 as a target
Reviews from the same group placed PE-22-28 in a broader program targeting K2P channels, including TREK-1 and TASK-3, in depression models (Borsotto et al., 2015). TREK-1’s roles in pain perception and neuroprotection mean that blocking it could have effects beyond the behavioral assays, a point any study design has to account for (Alloui et al., 2006).
What the evidence does not show
Nearly all published work on spadin and PE-22-28 comes from one research institute, and independent replication is limited. The peptide has been studied in mice and cell systems only. Rodent depression paradigms such as forced swim measure specific behaviors under stress and have well-known limits as predictors of anything beyond the model. Long-term studies of TREK-1 blockade, including effects on pain sensitivity, seizure thresholds or cardiac channels in vivo, have not been published for PE-22-28. No result here establishes an effect in people, and none describes the material sold here.
Regulatory status
PE-22-28 is not approved by the FDA for any use. Rogue Compounds sells it as a research reagent only.
Handling and storage in the lab
Lyophilized PE-22-28 should be kept sealed and refrigerated at 2–8°C (36–46°F), protected from light. Keeping the vial closed until use limits exposure to moisture and air, which matters for a tryptophan-containing peptide.
Sourcing and documentation
Rogue Compounds has PE-22-28 made in small batches. Every vial carries a batch number and a QR code that opens the independent U.S. testing lab’s own report for that batch. The same batch COA is posted on the product page and in the COA Library.
View PE-22-28 on Rogue Compounds
References
- Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M. Shortened spadin analogs display better TREK-1 inhibition, in vivo stability and antidepressant activity. Front Pharmacol. 2017;8:643. PMID 28955242
- Borsotto M, et al. Targeting two-pore domain K+ channels TREK-1 and TASK-3 for the treatment of depression. Br J Pharmacol. 2015;172:771-784. PMID 25263033
- Devader C, et al. In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin. Br J Pharmacol. 2015;172:2604-2617. PMID 25598009
- Alloui A, et al. TREK-1, a K+ channel involved in polymodal pain perception. EMBO J. 2006;25:2368-2376. PMID 16675954
Research use only. Rogue Compounds products are sold strictly for laboratory research. They are not for human or veterinary use, and nothing in this article is medical advice. The studies cited here describe published research, not this product or any use of it.