Tropical psychotria plants are a rich source for peptide inhibitors of human prolyl oligopeptidase.

“Tropical psychotria plants are a rich source for peptide inhibitors of human prolyl oligopeptidase. Hellinger R(1), Schwarz P(1), Dieringer J(1), Ebermann C(1), Jadhav KB(2), Muttenthaler M(2)(3), Gruber CW(4). Author information: (1)Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria. (2)Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, 1090, Vienna, Austria. (3)Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, Australia. (4)Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria. christian.w.gruber@meduniwien.ac.at. Peptides from natural sources have often served as valuable leads in drug discovery. Plant-derived protease inhibitors are a notable class, yet their distribution, diversity, and targets remain underexplored. Here, eleven tropical Psychotria species were screened for cyclic cysteine-rich peptides, with extracts showing concentration-dependent inhibition of human prolyl oligopeptidase (POP). Peptidomics combining mass spectrometry and transcriptome mining revealed multiple inhibitory peptides. From Psychotria solitudinum, which contained 37 peptides, a novel peptide (psysol 3) was purified and sequenced. Its synthetic analogue inhibited POP with an IC50 of ~ 1.3 µM. Sequence analysis and synthetic probes identified loop 3 as the inhibitory motif. Psysol 3 is a new probe for POP pharmacology and future structure-activity studies. © 2026. The Author(s). Conflict of interest statement: Declarations. Ethics approval and consent to participate: The research adhered to the Declaration of Helsinki and institutional protocols, receiving approval from the Ethical Board of the Medical University of Vienna (EK1548/2020). Prior to blood donation, volunteers gave written informed consent. No gender or sex analysis was conducted, as it is expected that human active serum will demonstrate uniform activity in both sexes. A total of six volunteers participated in the blood sample collection. Competing interests: The authors report there are no competing interests to declare.”