Recent progress of proline endopeptidase ligands and their effects on protein-protein interactions

Proline endopeptidase (PREP), as a serine protease, plays a crucial role in human physiology and pathology, and is intricately linked to the genesis and progression of a spectrum of illnesses. The fluorescent substrates currently used for PREP lack ideal specificity and are unable to specifically detect PREP activity under physiological conditions. This limitation, to some extent, hinders the in-depth investigation of its physiological and pathophysiological functions. Beyond its enzymatic capabilities, PREP's physiological functions extend to the modulation of protein-protein interactions (PPIs), a dimension whose significance is only beginning to be recognized, and investigations into how PREP inhibitors might influence these PPIs remain sparse. Therefore, based on the outline of the distribution and structural characteristics of PREP, this review systematically summarized the structure-activity relationship (SAR) of PREP ligands concerning their potency and specificity, the associated recognition mechanisms, as well as the regulatory impact of PREP ligands on PPIs. Finally, the obstacles and future prospects of PREP ligands were emphasized, in order to provide suggestions and help for the design and development of PREP specific substrates and inhibitors.