PE-22-28

Overview

PE-22-28 is a synthetic seven-amino-acid peptide (GVSWGLR) that blocks the TREK-1 (KCNK2) potassium channel. It is a shortened, more stable analog of spadin, a fragment cleaved from the propeptide of sortilin / neurotensin receptor-3 (NTSR3). Spadin was identified by Mazella and colleagues (CNRS, France) in 2010 as a fast-acting antidepressant candidate, and PE-22-28 was engineered by the same group as its minimal active fragment. All evidence is preclinical — rodent and in-vitro only; there are no human trials. It is a research compound, not an approved or clinically tested drug.

Mechanism

TREK-1 is a background ("leak") potassium channel that helps set neuronal excitability; mice lacking it are depression-resistant, which framed it as an antidepressant target. By blocking TREK-1, PE-22-28 reduces the channel's hyperpolarizing leak and increases firing of serotonergic neurons. In rodents this produces rapid antidepressant-type signaling overlapping with chronic SSRI effects (raised CREB phosphorylation, BDNF, hippocampal neurogenesis). It is markedly more potent than spadin (rodent IC50 ~0.12 nM) and, in vitro, selective for TREK-1 with no hERG activity — a favorable but untranslated preclinical signal.

Clinical evidence

There is no clinical evidence in humans — no completed or registered human trials. The supporting data are rodent behavioral assays (forced swim, learned helplessness, novelty-suppressed feeding) and in-vitro electrophysiology. The only human-derived observations are biomarker studies showing altered sortilin / propeptide levels in depressed patients — which implicate the pathway but say nothing about PE-22-28's safety or efficacy in people. The compound remains entirely at the preclinical stage.

Safety profile

PE-22-28 has no human safety data — it has never been given to humans in a controlled study, so its tolerability, dosing and long-term effects are unknown. The preclinical record is mildly reassuring (TREK-1 selectivity, no hERG effect, no overt adverse effects in short studies), but cannot substitute for clinical testing, and TREK-1 is expressed well beyond mood circuits (pain, vasculature, ischemia), so the consequences of pharmacologic blockade in humans are uncharacterized. The "~23 h" figure is a rodent duration-of-effect, not a measured half-life. Research-use only; not WADA-listed; nothing here is medical guidance.

Compare

• vs Selank

  A neuropeptide also studied for mood/anxiety, but Selank has at least some Russian human use whereas PE-22-28 is purely preclinical.

• vs Semax

  Another neuro-active peptide with mood/cognition framing; unlike PE-22-28 it has Russian clinical use, though Western evidence is still weak.