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Neuropeptides

PE 22-28

Also known as PE-22-28, PE22-28, GVSWGLR, spadin fragment 22-28, shortened spadin analog

Preclinical only

Peptide inhibitor of the TREK-1 (K2P2.1) two-pore-domain potassium channel. Investigational, preclinical antidepressant lead.

Not FDA-approved. Not on FDA's 503A category lists (May 14, 2026). Source, May 14, 2026

Identity. PE 22-28 most likely refers to the 7-residue sortilin-propeptide fragment (residues 22-28), GVSWGLR. It is a shortened analog of spadin (PE 12-28) described by Djillani et al. 2017. Related but distinct molecules include G/A-PE 22-28 (Gly22 to Ala), biotinylated-G/A-PE 22-28, PI-PE 22-28 (PE 20-28), and mini-spadin (Pietri 2019). It is not established that mini-spadin is the same molecule as PE 22-28, so mini-spadin data are not used for PE 22-28. The 14-23 h half-effect times in Djillani 2017 were measured for G/A-PE 22-28 and biotinylated-G/A-PE 22-28 only, not for unmodified PE 22-28. Data for any analog do not apply to GVSWGLR.

At a glance

These dosages are a helpful guide, not a prescription. Every clinician is expected to do their own due diligence before prescribing.

No established human dose

Preclinical only. PE 22-28 (GVSWGLR) blocked TREK-1 in HEK cells (IC50 about 0.1 nM). In mice, acute intraperitoneal doses of 3.0-4.0 ug/kg reduced forced-swim immobility. That range covers the three spadin analogs together; PE 22-28 itself was given at 3.0 ug/kg in the corticosterone model. Four days of dosing raised hippocampal BrdU-positive cells. The only primary paper comes from the originating lab. There is no human study, no FDA label, and no clinician protocol with a traceable source, so no human dose can be cited. Mouse doses are per kg, depend on the route, and apply to the analog class. They are not human doses.

No human dosing exists; all dosed data are mouse studies per kg, and a 10 mg vial cannot be scaled from them.
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Dosing detail

Clinical practice

Clinical practice

No peer-reviewed review, pharmacy or clinic protocol, professional education material or textbook giving human dosing for PE 22-28 was found. Web pages that list regimens are unsourced vendor or community content, and they disagree with each other. One page lists 0.1-10 mg/kg and 1-5 mg/kg twice daily, which the 2017 mouse paper does not contain (it uses ug/kg). Another lists 3-4 mcg/kg intraperitoneal mouse doses that match the paper, but these are mouse doses, not a human protocol. No practice number is reported. The only dosed data are mouse studies, all per kg of mouse and attributed to the spadin-analog class (PE 22-28, G/A-PE 22-28, biotinylated-G/A-PE 22-28) unless stated. Doses were intraperitoneal 3.0-4.0 ug/kg (acute and 4 days; PE 22-28 itself 3.0 ug/kg intraperitoneal in the corticosterone model) and gavage 1 mg/kg, a roughly 330-fold difference by route, per PMID 28955242. The paper's Fig. 5 legend lists intraperitoneal 100 ug/kg, so the paper is inconsistent on this point. Do not scale these doses to humans. A 10 mg vial is 10,000 ug, and scaling 1 mg/kg to a 70 kg adult gives 70 mg, which exceeds the whole vial. Do not offer a dose calculator output for this compound. A related spadin-derived peptide (mini-spadin; its identity with PE 22-28 is not established) showed biphasic TREK-1 effects in mice: activation at 0.03 ug/kg and inhibition at 3 ug/kg (PMID 31325429). The dose-response may not be linear, so no low-dose strategy can be assumed safe.

Safety

Serious warnings

  • No FDA label or boxed warning exists for PE 22-28. The supplier states the product is not for human or veterinary use. No human safety data were found.3
  • Mechanism-based concern, extrapolated from knockout mice and not observed with PE 22-28. Mice lacking TREK-1, the channel PE 22-28 blocks, show increased sensitivity to ischemia and epilepsy (Heurteaux 2004). No seizure or ischemia safety study of PE 22-28 exists.4
  • The originating lab states that TREK-1 has an important role in atrial fibrillation, pulmonary arterial hypertension and ventricular arrhythmia. The cardiac safety of PE 22-28 has not been studied in vivo.5

Contraindications

  • None established. PE 22-28 has not been evaluated in humans, and the absence of a listed contraindication is not clearance. Caution or avoidance is theoretically reasonable with seizure disorder, prior stroke or TIA, ischemic cerebrovascular disease, or a history of cardiac arrhythmia. This is inferred from TREK-1 knockout and channel-biology data only.4

Adverse effects

  • No adverse-event data exist in humans. In HEK cells, the spadin-analog class (PE 22-28 used as the representative for the other K2P channels) did not alter hERG current at 10 uM. K2P selectivity was tested against four channels at a single 100 nM concentration. No in vivo ECG or QT study was found. The authors' statement that analogs would be 'devoid of side effects' is an expectation, not a measured outcome.5
  • The parent compound spadin (not PE 22-28) was reported to potentiate insulin secretion and raise glucose-stimulated plasma insulin in mice. This is a TREK-1 class effect that has not been tested for PE 22-28.6

Monitoring

  • No validated monitoring exists. The items below are inferred from preclinical class data and are not a protocol: glucose (spadin raised glucose-stimulated insulin in mice); seizure history, baseline ECG and cardiac history (TREK-1 knockout and channel-biology data); mood and suicidality assessment if used for depressive symptoms.6

Handling

Storage before mixing

-20 C (supplier specification for the acetate salt, purity 98% or higher; not a pharmacy beyond-use date)3

Evidence

Preclinical only. PE 22-28 (GVSWGLR) blocked TREK-1 in HEK cells (IC50 about 0.1 nM). In mice, acute intraperitoneal doses of 3.0-4.0 ug/kg reduced forced-swim immobility. That range covers the three spadin analogs together; PE 22-28 itself was given at 3.0 ug/kg in the corticosterone model. Four days of dosing raised hippocampal BrdU-positive cells. The only primary paper comes from the originating lab. There is no human study, no FDA label, and no clinician protocol with a traceable source, so no human dose can be cited. Mouse doses are per kg, depend on the route, and apply to the analog class. They are not human doses.

Mechanism

PE 22-28 blocks the TREK-1 potassium channel. In hTREK-1/HEK cells it inhibited arachidonic-acid-activated TREK-1 current with an IC50 of about 0.1 nM (0.10-0.12 nM across the paper text), versus 40-60 nM for spadin. At 100 nM it did not change TREK-2, TRAAK, TRESK or TASK-1 currents. The spadin-analog class did not change hERG current at 10 uM, with PE 22-28 used as the representative for the other channels. In mice (intraperitoneal, 4 days) it increased hippocampal BrdU-positive cells. In cultured mouse cortical neurons (0.1 uM, up to 36 h) the analogs increased PSD-95 expression. The PSD-95 result is in vitro, not in vivo.35

Availability

Amounts offered

  • 10 mg

Custom strengths on request.

References

According to PubMed

  1. 1PE-22-28 Dosing Protocols and Administration | Peptide Protocol Wikipeptideprotocolwiki.com, updated February 12, 2026; vendor/community compilation, no reference list, 2026
  2. 2PE-22-28 Dosing: What Clinics Prescribe and What to Expect (2026)mypeptidematch.com, PeptideClinicLocator Editorial Team, February 17, 2026; vendor/referral content, 2026
  3. 3PE 22-28 (acetate), Item No. 39986Cayman Chemical product page (research-chemical supplier; sequence, storage, use warning), 2026
  4. 4TREK-1, a K+ channel involved in neuroprotection and general anesthesia.EMBO J 2004;23(13):2684-95 (Heurteaux C et al.) - TREK-1 knockout mice, not PE 22-28, 2004
  5. 5Shortened Spadin Analogs Display Better TREK-1 Inhibition, Stability and Antidepressant Activity.Front Pharmacol 2017;8:643 (Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M), 2017
  6. 6Potentiation of Calcium Influx and Insulin Secretion in Pancreatic Beta Cell by the Specific TREK-1 Blocker Spadin.J Diabetes Res 2016;2016:3142175 (Hivelin C et al.) - spadin, not PE 22-28, 2016
  7. 7First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides.Neuropharmacology 2019;158:107715 (Pietri M et al.) - mini-spadin; identity with PE 22-28 unconfirmed, 2019
  8. 8Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin.Pharmacol Ther 2018;194:185-198 (Djillani A et al.) - review, 2018
  9. 9Bulk Drug Substances Used in Compounding Under Section 503A of the FD&C ActU.S. FDA; page content current as of 05/14/2026, 2026
  10. 10Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety RisksU.S. FDA; page content current as of 04/22/2026, 2026

Last reviewed 2026-10-14. 17 figures checked against their sources. How this works