PE 22-28

What Is PE 22-28?

PE 22-28 is a seven-amino-acid synthetic peptide derived from the propeptide of sortilin (positions 22 to 28 of the parent PE sequence), engineered by Mazella, Borsotto, and colleagues at the Institut de Pharmacologie Moleculaire et Cellulaire as a shorter, more stable, and more potent analogue of spadin. It selectively inhibits TREK-1 (TWIK-related potassium channel 1), a two-pore-domain potassium channel that, when overactive, dampens serotonergic neurotransmission in the dorsal raphe and prefrontal cortex.

TREK-1 knockout mice are resistant to depression-like behaviour and show enhanced serotonin signalling, the genetic validation behind the compound class. By blocking TREK-1, PE 22-28 releases the brake on serotonergic firing and downstream BDNF expression, producing antidepressant-like effects in mice within four days, compared with three to four weeks for fluoxetine, alongside measurable hippocampal neurogenesis. PE 22-28 is roughly 300- to 500-fold more potent at TREK-1 than spadin (IC50 about 0.12 nM versus 40 to 60 nM), with a duration of action extended from about 7 hours to about 23 hours in the rodent work. No human trial data exist.