Prolyl oligopeptidase (POP) (POP)

Prolyl oligopeptidase (POP), also known as prolyl endopeptidase (PREP), is a large cytosolic serine protease that specifically cleaves peptide bonds on the carboxyl side of proline residues in peptides shorter than 30 amino acids [1]. It is highly expressed in the brain and is involved in the maturation and degradation of neuropeptides such as substance P, neurotensin, and vasopressin [2]. Beyond its catalytic role, POP has been identified as a key modulator of alpha-synuclein aggregation and autophagy, making it a significant therapeutic target for Parkinson's disease and other neurodegenerative disorders [3]. While traditional drug discovery has focused on the enzyme's active site, recent research has highlighted an alternative allosteric site located within the β-propeller domain [4]. Targeting this allosteric site offers a novel mechanism to regulate POP's protein-protein interactions and enzymatic activity with potentially improved selectivity and reduced off-target effects compared to active-site inhibitors [2]. This approach is currently being explored to develop treatments for cognitive deficits and synucleinopathies [4]. The β-propeller domain acts as a gatekeeper for the active site, and allosteric ligands can influence the opening and closing of this domain [3]. Consequently, allosteric modulators of POP represent a promising class of compounds for precision medicine in neurology [4].

Other names

Prolyl endopeptidasePREPPost-proline cleaving enzymePE

Allosteric modulation of enzyme activity and protein-protein interactions, specifically targeting the β-propeller domain to inhibit alpha-synuclein aggregation and regulate neuropeptide processing.