NOT FOR HUMAN CONSUMPTION

PE-22-28 is a heptapeptide with the sequence GVSWGLR (Gly–Val–Ser–Trp–Gly–Leu–Arg). It is widely described as the smallest active fragment derived from the endogenous peptide spadin, retaining potent antagonism of the TREK-1 (KCNK2) two-pore domain potassium channel.

Nomenclature origin: “PE(22-28)” refers to a peptide fragment numbering used in the parent propeptide context described in patents/literature; the peptide is associated with sortilin/NTSR3 propeptide → spadin → PE-22-28 fragments in the discovery chain.

2) Target biology: why TREK-1 matters

TREK-1 (KCNK2) is a background/leak K⁺ channel that helps set resting membrane potential and dampens excitability. In many neuron types, inhibiting TREK-1 tends to increase excitability and can shift network activity in ways that have been explored for antidepressant-like effects, neuroplasticity, and post-injury recovery.

PE-22-28’s importance is that it is a high-potency TREK-1 inhibitor reported at sub-nanomolar IC₅₀ (~0.12 nM) in vendor-compiled pharmacology summaries (which typically trace back to primary literature).

3) Molecular mechanism of action

3.1 Receptor/channel pharmacodynamics

• Primary target: TREK-1 (KCNK2) inhibition (functional antagonism).

• Immediate electrophysiologic consequence (conceptual): reduced K⁺ leak conductance → membrane depolarization tendency → greater neuronal responsiveness (cell-type and state dependent).

3.2 Downstream neurobiology (hypothesis map)

Important interpretation constraint: Many of the “downstream” benefits are preclinical outcomes; PE-22-28 is best thought of as a research tool compound for TREK-1 biology and related phenotypes, not as a clinically validated therapy.

4) Chemistry and structure

• Sequence: GVSWGLR

• CAS: commonly listed as 1801959-12-5 in reagent catalogs.

• Design notes: Patents describe PE(22-28) as a base peptide used to design analogs (e.g., N-terminal modifications, substitutions, C-terminal derivatizations) to tune activity, stability, or labeling.

Quality-control note (practical): marketplace listings are not always consistent (some sites misreport the sequence). When writing professionally, it’s worth stating that authentic PE-22-28 is GVSWGLR, consistent with multiple reagent suppliers and patent language.

5) Pharmacokinetics and exposure considerations

There is no drug-label PK because PE-22-28 is not an approved medicine. As a 7-aa peptide, key PK realities typically include:

• rapid proteolysis in plasma/tissues unless formulated/modified,

• route dependence (systemic exposure and CNS exposure can differ substantially),

• possible short half-life without stabilization strategies.

Patents explicitly discuss chemical modifications/analogs, which is often a sign that native peptide stability and deliveryare important development constraints.

6) Evidence base (what’s actually supported)

6.1 Strongest, most “anchored” claims

• Potent TREK-1 inhibition (IC₅₀ around 0.12 nM) and use as a pharmacological tool.

• Preclinical outcomes reported in rodent models (stroke recovery, hippocampal neurogenesis; β-cell apoptosis reduction in ischemia contexts) in supplier summaries referencing underlying studies.

6.2 What is not established

• Robust, replicated human clinical efficacy for depression, cognition, stroke recovery, or metabolic endpoints.

• Long-term safety in humans at therapeutically relevant exposures.

7) Safety and tolerability: scientific framing

Because PE-22-28 is investigational/research, safety is best discussed as mechanism-informed risk hypotheses:

Potential risks to consider in research translation:

• CNS excitability shifts: TREK-1 inhibition can alter neuronal firing thresholds; depending on circuits, this can theoretically increase risk of adverse neuropsychiatric or sleep effects (speculative without human trials).

• Off-tissue physiology: TREK-1 is expressed in multiple tissues; systemic dosing may have non-CNS electrophysiologic effects (context dependent).

• Immunogenicity/impurities: small peptides are generally less immunogenic than proteins, but impurities and formulation can drive reactions—especially outside GMP medicine pathways.

8) Regulatory status and real-world positioning

PE-22-28 is sold primarily as a research reagent and is not FDA/EMA-approved for therapeutic use.

9) Future directions (what would make PE-22-28 “clinical-grade”)

1. Validated PK/PD: demonstrate exposure and target engagement (TREK-1 occupancy/functional biomarkers) in humans.

2. Route/formulation optimization: stabilizing analogs and delivery approaches (already implied by patent-driven analog design).

3. Function-first clinical endpoints: if pursued for mood or recovery, trials should prioritize clinically meaningful outcomes (e.g., depressive symptom scales, functional recovery metrics) plus mechanistic neuroplasticity readouts.

Selected references (most load-bearing)

• TREK-1 inhibition potency and preclinical effects summary:

• Sequence/identity and “smallest active spadin fragment” description:

• Patent text specifying GVSWGLR and analog design built on PE(22-28):

• Additional catalog confirmations (CAS/identity; research tool framing)