PE-22-28: The Complete Guide
A 7-amino-acid peptide derived from Spadin — one of the most potent known inhibitors of the TREK-1 potassium channel: in patch-clamp recordings (Djillani et al., 2017) it inhibits TREK-1 at more than 300-fold lower concentrations than its parent compound.
What is PE-22-28?
PE-22-28 is a synthetic heptapeptide — just 7 amino acids — developed as a shortened, optimised version of Spadin, a naturally occurring peptide derived from the protein sortilin. Spadin was characterised as a TREK-1 potassium channel blocker, drawing research attention because TREK-1 knockout mice showed resistance to depressive-like behaviour in research models.
The challenge with Spadin in research applications was that it degraded quickly in the body (approximately 7 hours of activity) and was not particularly potent. Researchers at the University of Nice Sophia Antipolis set out to identify the smallest, most active fragment of Spadin — and PE-22-28 was the result. At just 7 amino acids, it blocks TREK-1 with an IC50 of 0.12 nM against 40–60 nM for Spadin, measured by whole-cell patch-clamp on TREK-1-expressing cells — a concentration more than 300-fold lower, in the authors’ own terms (Djillani et al., 2017).
What makes PE-22-28 distinctive in the research peptide space is its selectivity. Research suggests it blocks TREK-1 specifically, without affecting related potassium channels (TREK-2, TRAAK, TRESK, TASK-1) or the cardiac hERG channel. This precision targeting, combined with preclinical research data on neurogenesis and mood-related research models, has positioned PE-22-28 as a notable research compound in the neuropeptide space.
Research Applications
Research on PE-22-28 spans TREK-1 channel pharmacology, hippocampal neurogenesis, the broader sortilin-spadin signalling family, and the structural-activity relationship work that produced PE-22-28 from the longer Spadin parent peptide.
Research suggests PE-22-28 stimulates neurogenesis — the formation of new neurons — through TREK-1 channel inhibition. TREK-1 acts as a regulator of neuronal excitability, and research suggests its inhibition is associated with neural growth signalling in animal models.
In patch-clamp recordings on TREK-1-expressing cells, PE-22-28 inhibits the channel at concentrations as low as 0.12 nanomolar — one of the most potent TREK-1 inhibitors characterised in the published literature, and more than 300-fold lower than its Spadin parent peptide (Djillani et al., 2017).
TREK-1 channels are studied in the context of neuronal excitability and serotonergic signalling. Research suggests PE-22-28 inhibition of TREK-1 affects these pathways — an active area of mood-related research in animal models.
Beyond neurogenesis, research suggests PE-22-28 promotes synaptogenesis — the formation of new synaptic connections between neurons. Research models use synaptogenesis as a structural marker for neural plasticity studies.
PE-22-28 is a shortened, more potent analogue of Spadin — the first identified natural TREK-1 blocker, derived from sortilin processing. Research suggests the shortened sequence retains TREK-1 selectivity while improving potency and metabolic stability.
Research suggests PE-22-28 produces measurable changes in neurogenesis markers within days in animal models — a profile that distinguishes it from many compounds in this research area in terms of onset timing.
How PE-22-28 Works
The PE-22-28 mechanism centres on a single specific target — the TREK-1 potassium channel — with downstream effects extending across multiple neural research pathways:
TREK-1 blockade: TREK-1 is a two-pore-domain potassium channel that is normally open under resting conditions, allowing potassium ions to flow out of neurons and maintaining a less excitable state. Research suggests PE-22-28 inhibits this channel, increasing neuronal excitability and responsiveness. In the dorsal raphe nucleus — where serotonin-producing neurons originate — research suggests this inhibition enhances serotonergic transmission.
Neurogenesis pathway: Research suggests the downstream effect of TREK-1 inhibition includes increased expression of neurotrophic factors — proteins that support neuronal growth, survival, and differentiation. This is associated with hippocampal neurogenesis — the formation of new neurons in the brain region central to memory and emotional regulation research. Hippocampal neurogenesis is studied as a structural marker in mood-related research models.
Structure-activity refinement: Research suggests PE-22-28 retains the core TREK-1 binding sequence of Spadin while shedding non-essential amino acids. The result is a peptide that inhibits TREK-1 at more than 300-fold lower concentrations in the same patch-clamp assay (Djillani et al., 2017), with no measurable effect on related channels (TREK-2, TRAAK, TRESK, TASK-1) or the cardiac hERG channel. Modified analogues such as G/A-PE 22-28 have been characterised in research with extended duration of action.
Storage Guidelines
Store at 2–8°C in a cool, dry place. Protect from light and moisture. Refrigerate once in solution form.
Frequently Asked Questions
Technical Specifications
Compiled by the Southern Pacific Labs research team. Last updated April 2026.
Published References
- Djillani A, Pietri M, Moreno S, et al. “Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity.” Frontiers in pharmacology, 2017. PubMed
- Pietri M, Djillani A, Mazella J, et al. “First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides.” Neuropharmacology, 2019. PubMed
- Daziano G, Blondeau N, Béraud-Dufour S, et al. “Sortilin-derived peptides promote pancreatic beta-cell survival through CREB signaling pathway.” Pharmacological research, 2021. PubMed
- Djillani A, Pietri M, Mazella J, et al. “Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin.” Pharmacology & therapeutics, 2019. PubMed
Browse all PE-22-28 research on PubMed →
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