What is PE22–28?

By Cocer Peptides      1 month ago

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Overview of PE22–28

PE22–28 is a 7-amino acid peptide designed based on research into Spadin (PE 12–28). Depression, a mental disorder affecting approximately 20% of the global population, is currently treated with antidepressants that suffer from issues such as delayed onset of action and severe side effects. Spadin is described as an endogenous peptide with antidepressant activity that specifically blocks the TREK-1 channel, but its activity disappears within 7 hours after administration. To enhance Spadin's stability and bioavailability in vivo, researchers screened its analogs and derivatives, studying Spadin's blood degradation products, and ultimately designed PE22-28.

Figure 1 Spadin-analog specificity. (A–D) PE 22-28 was used as the representative peptide for testing the specificity of spadin-analogs vs. other K2P channels, TREK-2 (A), TRAAK (B), TRESK (C), and TASK-1 (D).  

The action of PE22-28

Effect on TREK-1 Channels

In vitro studies using patch-clamp technology on hTREK-1/HEK cells demonstrated that PE22-28 exhibits better specificity and affinity for TREK-1 channels compared to Spadin. Specific data show that the IC₅₀ of PE22-28 is 0.12 nM, while that of Spadin is 40–60 nM. This means that under the same conditions, PE22-28 can act on the TREK-1 channel more effectively at lower concentrations, thereby exerting its biological effects more precisely. The study also noted that under the same conditions, different modifications at the N- or C-terminus of PE22-28 can maintain or eliminate TREK-1 channel activity without affecting its affinity for the TREK-1 channel. This unique regulatory mechanism of channel activity and affinity provides important clues for further research into its mechanism of action and drug development.

Antidepressant effects in vivo

Behavioral model validation: In depressive behavior models such as the forced swim test, the antidepressant properties of PE22-28 and its derivatives were confirmed. Mice treated with Spadin analogues (including PE22-28) exhibited a significant reduction in immobility time. Immobilization time is an important indicator of depressive-like behavior in mice during the forced swim test, and a reduction in immobilization time indicates a decrease in depressive-like behavior, suggesting that PE22-28 has antidepressant effects. In the novelty-inhibited feeding test after 4 days of subchronic treatment, PE22-28 significantly reduced the latency period for mice to consume food pellets. The novelty-inhibited feeding test is an experimental method to assess mice's willingness to eat in a new environment. A shorter latency period indicates reduced anxiety and depression-related behaviors in mice, further confirming the antidepressant effects of PE22-28.

Effects on neurogenesis and synaptogenesis: After just 4 days of treatment, PE22-28 and its analogues induced neurogenesis, with G/A-PE22-28 showing particularly significant effects. Neurogenesis plays a key role in the pathogenesis of depression and treatment response, and the generation of new neurons helps improve neural function and mood state. In mouse cortical neurons, PE22-28 and its derivatives also enhanced synaptogenesis, as measured by increased PSD-95 expression levels. PSD-95 is a protein associated with the postsynaptic dense region, and increased expression levels indicate enhanced synapse formation and function, facilitating information transmission between neurons and neural circuit remodeling, which is of significant importance for improving depressive symptoms.

Advantages in duration of action: Compared to Spadin, the duration of action of PE22-28 and its analogues is significantly improved. Spadin loses its activity 7 hours after administration, while the duration of action of PE22-28 can reach up to 23 hours. A longer duration of action means that its biological effects can be sustained for a longer period in vivo, reducing the frequency of administration and improving patient compliance, which has important practical implications for clinical treatment.

Applications of PE22-28

Potential applications in depression treatment: Given PE22-28's excellent performance in antidepressant behavioral models, its unique mechanism of action on the TREK-1 channel, and its positive effects on neurogenesis and synaptogenesis, it represents a promising molecule with the potential to replace Spadin in depression treatment. The emergence of PE22-28 offers new treatment options for depression. It has become an important direction for the development of the next generation of antidepressant drugs. Through further research and development, optimizing its drug formulation and administration methods, it is expected to provide more effective treatment options for patients with depression.

Source

[1] Djillani A, Pietri M, Moreno S, et al. Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity[J]. Frontiers in Pharmacology, 2017,8:643.DOI:10.3389/fphar.2017.00643.

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