PE-22-28 vs Selank.

PE-22-28 is a synthetic seven-residue peptide corresponding to residues 22 to 28 of spadin, itself a fragment derived from the sortilin propeptide (also called neurotensin receptor-3). It was developed as a shortened, more stable analog of spadin intended to block the TREK-1 potassium channel. It has been studied as a fast-acting antidepressant candidate in rodent models. It is a preclinical research compound with no human data.

Selank is a synthetic heptapeptide (Thr-Lys-Pro-Arg-Pro-Gly-Pro) developed at the Institute of Molecular Genetics of the Russian Academy of Sciences, with the laboratory designation TP-7. It is a stabilized analog of tuftsin, an endogenous immunomodulatory tetrapeptide (Thr-Lys-Pro-Arg) derived from the Fc region of immunoglobulin G; the added Pro-Gly-Pro tail confers resistance to enzymatic degradation. It is studied primarily as an anxiolytic and nootropic agent and is most associated with Russian neuropharmacology research.

PE-22-28 acts by inhibiting the TREK-1 two-pore-domain potassium channel, which is implicated in mood regulation and in resistance to conventional antidepressants. By blocking TREK-1, it is proposed to increase serotonergic neurotransmission and promote hippocampal neurogenesis. Reported potency is high, with a sub-nanomolar IC50 and improved metabolic stability compared with spadin. These effects are characterized in cell and animal systems.

Selank's parent peptide tuftsin acts on immune cells, and Selank retains immunomodulatory activity while shifting toward neuromodulation. Proposed central mechanisms include modulation of monoamine systems (serotonin, dopamine, noradrenaline) and interaction with the GABAergic and enkephalin/opioid systems; Selank has been reported to inhibit enkephalin-degrading enzymes, prolonging the action of endogenous enkephalins. It has also been reported to influence expression of brain-derived neurotrophic factor (BDNF) and to alter cytokine balance (e.g., IL-6 and interferon-related signaling). These mechanisms are largely characterized in rodent and in vitro models rather than established in humans.

Evidence for PE-22-28 is preclinical only. In the foundational study, shortened spadin analogs including PE-22-28 showed stronger TREK-1 inhibition, longer in-vivo stability and antidepressant-like activity in behavioral tests such as forced swim and novelty-suppressed feeding, along with induction of neurogenesis after a short treatment course (Djillani et al., Frontiers in Pharmacology 2017). A review of TREK-1 blockers situates spadin and its analogs within antidepressant drug discovery (Djillani et al., Pharmacology and Therapeutics 2019). Related work describes the sortilin/NTSR3 origin of spadin and its role in the membrane expression of TREK-1, which supplies the mechanistic rationale for the shortened analogs (Frontiers in Pharmacology, 2018). Separate mouse work using genetic and pharmacological inhibition of TREK-1 reported changes in depression-related behavior and hippocampal neuronal plasticity (CNS Neuroscience and Therapeutics, 2021); that work supports the target as biologically interesting but does not test this peptide. The design of the supporting studies limits the conclusions available. They are rodent experiments run in academic laboratories, largely the group that originated spadin, over short treatment courses. The behavioral readouts are screening assays rather than models of depression: forced swim, tail suspension and novelty-suppressed feeding are sensitive to known antidepressants, which makes them useful filters, but a long list of compounds that performed well in them has failed in human trials. The reports are not blinded multi-centre studies, are not pre-registered, and have not been replicated head to head by an independent group. No completed or registered human clinical trial exists for PE-22-28. There is consequently no Phase 1 safety or tolerability dataset, no human pharmacokinetic profile, no measured central nervous system exposure in people, and no published toxicology package. This is a weaker position than that of compounds it is informally compared with: approved rapid-acting antidepressants such as esketamine were established through randomized, placebo-controlled trials with standard depression rating scales before approval, and even TREK-1 or novel-mechanism candidates that ultimately failed generally reached Phase 1 and produced human exposure and tolerability data. Antidepressant-like signals in rodents do not establish human efficacy or safety.

The great majority of Selank evidence is preclinical (rodent and in vitro), covering anxiolytic-like behavior, stress models, immune/cytokine modulation, and tissue effects under chronic stress (e.g., Bull Exp Biol Med studies on rat intestine and liver under restraint/foot-shock stress, and a cytokine study under 'social' stress). Human clinical data are limited and come almost entirely from Russian-language trials and registry approval rather than large, independently replicated, placebo-controlled studies indexed in Western literature; reported uses include generalized anxiety disorder and asthenic/neurasthenic conditions. A frequently cited molecular review (Protein and Peptide Letters, 2018, PMID 30255741) summarizes the proposed biology. Overall, robust, independently replicated human efficacy data are thin, and mechanistic plausibility should not be read as proven clinical benefit.

No human safety data exist for PE-22-28; all information comes from short-term rodent studies. There is no published Phase 1 tolerability study, no human pharmacokinetic or elimination data, no immunogenicity assessment, and no repeat-dose or reproductive toxicology package in the public literature. Because TREK-1 is expressed in tissues outside the brain, including cardiovascular, smooth muscle and immune-related tissues, systemic and off-target effects are theoretically possible; the channel also contributes to cellular responses to mechanical and thermal stimuli, so blocking it chronically could have consequences that short rodent behavioral experiments were never designed to detect. Effects on mood-related circuitry are themselves a caution: psychoactive compounds acting on serotonergic signaling and neurogenesis can produce agitation, sleep disruption or worsening mood, and no monitored human exposure exists to characterize any of this. Purity, identity and long-term toxicology of material sold as a research chemical are not controlled. Such products are made outside pharmaceutical good manufacturing practice, carry no verified certificate of analysis for peptide content, impurity profile or endotoxin, and are labeled for laboratory use only. Buyers cannot confirm what the vial holds or whether a reconstituted solution is sterile. The lack of reported adverse events reflects the lack of supervised human use rather than a safety record. With no clinical trials, no pharmacovigilance reporting and no registry, harms occurring in unsupervised use would not be captured. It is not a medicine and is not intended for human use.

Published reports, mostly from the developing Russian groups, describe Selank as generally well tolerated with a notably low sedation, dependence, and withdrawal profile compared with benzodiazepines, but rigorous long-term and large-sample safety data from independent groups are lacking. Because much of the safety record comes from the originating institutions and small studies, the true adverse-event and long-term safety profile in humans is not well established. As a peptide typically administered intranasally in research, purity, contamination, and product-quality concerns apply to non-pharmaceutical material. It has not undergone the comprehensive safety review required for major regulatory approval outside its country of origin.

PE-22-28 is not approved by the FDA or any other regulator and has no approved medical use. It exists only as a preclinical research compound. This summary is educational and includes no dosing guidance.

Selank is reported to have been registered/approved in Russia (around 2009) for anxiety and asthenic conditions, marketed as an intranasal preparation. It is not approved by the US FDA and is not an approved drug in the EU; outside Russia it is effectively investigational and is widely sold as a research-use-only / not-for-human-consumption chemical. It is not a controlled substance and is not a standard WADA-prohibited agent, but its unapproved status means quality and legality vary by jurisdiction.