Prolyl oligopeptidase (POP, also referred to as PREP) and fibroblast activation protein-(FAP, also referred to as seprase) are homologous serine proteases whose function consists of cleaving short peptides at the C-terminal end of proline residues. POP was discovered in the mid-70's, and its high concentration in the central nervous system (CNS) immediately drew attention; early studies associated POP protease activity to neuropeptides and peptide hormones. Inhibition of this protease activity was first investigated with the reversible covalent inhibitor 1 over thirty years ago (Figure ). However, after significant targeted research and unsuccessful clinical trials, this progress reached a plateau (Figure ). In more recent years, a second boost in the development of POP inhibitors has occurred, and their potential in Alzheimer's disease (AD) and Parkinson's disease (PD) has been under further investigation. More specifically, about 10 years ago, Lambeir and co-workers first linked POP to α-synuclein (aSyn) aggregation, a hallmark of PD, and Myöhänen and co-workers revealed the colocalization of POP with aSyn, amyloid beta (Aβ), and the tau protein in brain samples from patients with PD or AD. The link between POP and aSyn aggregation was further supported by extensive studies by Myöhänen and co-workers who first showed that aggregation is induced by POP-aSyn protein-protein interaction and is unrelated to the protease activity of POP. The same group also demonstrated the effect of KYP-2047, a POP inhibitor (Figure ), on aSyn aggregate clearance and the restoration of motor behavior in mouse models, while Lee and co-workers identified POP inhibitors and confirmed their effect on aSyn expression. In 2011 then in 2015, work by Lambeir then Savolainen et al. suggested that POP interacts with aSyn serving as nucleation point, hence inducing aggregation. More unexpectedly, they observed that KYP-2047 modulates the shape of POP and reduces its ability to interact with aSyn and reduce its aggregation. Using a combination of NMR and small angle Xray scattering, Giralt and co-workers revealed that POP inhibitors significantly impact this protein dynamics. In agreement with Savolainen et al.'s observations, they propose that while POP exists as an equilibrium of open and close conformations necessary to induce aSyn aggregation, POP bound to an inhibitor is more rigid adopting primarily the closed conformation which does not induce aggregation.