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

Abstract 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 IC 50 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.