PE-22-28

PE-22-28 is a synthetic heptapeptide derived from the propeptide domain of sortilin (specifically residues 22-28), designed as an optimized analogue of spadin, a natural TREK-1 potassium channel blocker. It was developed by researchers at the Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) in France as part of a program to create novel, fast-acting antidepressant candidates that bypass the slow onset of action characteristic of SSRIs and other monoamine-based antidepressants.

PE-22-28 represents a conceptually distinct approach to treating depression. Rather than modulating serotonin, norepinephrine, or dopamine reuptake, it targets TREK-1 (TWIK-related potassium channel 1), a two-pore domain potassium channel that regulates neuronal excitability in mood-related brain circuits. TREK-1 knockout mice are naturally resistant to depression-like behaviors, and pharmacological blockade of TREK-1 produces antidepressant effects within days rather than weeks in rodent models.

PE-22-28 blocks TREK-1 potassium channels by binding to an extracellular site on the channel protein, preventing potassium efflux and increasing neuronal excitability in serotonergic and other mood-regulating neurons. TREK-1 channels are widely expressed in the brain, with high density in the prefrontal cortex, hippocampus, and dorsal raphe nucleus — regions implicated in depression. Under normal conditions, TREK-1 generates a background leak current that dampens neuronal excitability. In depression, TREK-1 overactivity may contribute to reduced serotonergic output from the raphe nucleus.

By blocking TREK-1, PE-22-28 increases firing rates in serotonergic neurons, enhancing 5-HT release in terminal fields including the hippocampus and prefrontal cortex. This produces rapid increases in hippocampal neurogenesis and synaptogenesis — processes thought to underlie the therapeutic effects of antidepressants. The speed of PE-22-28's behavioral effects (4 days vs 14-21 days for SSRIs in rodent models) may reflect the fact that TREK-1 blockade directly increases neuronal excitability rather than waiting for homeostatic adaptation to reuptake inhibition. PE-22-28 has approximately 10-fold greater potency than its parent compound spadin, with an IC50 of approximately 40nM against TREK-1.