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

doi:10.1007/s13659-026-00598-z

Natural Products and Bioprospecting ›› 2026, Vol. 16 ›› Issue (4): 54-54.DOI: 10.1007/s13659-026-00598-z

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

Roland Hellinger¹, Paula Schwarz¹, Jonathan Dieringer¹, Carina Ebermann¹, Kirtikumar B. Jadhav², Markus Muttenthaler^2,3, Christian W. Gruber¹

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

Received:2025-12-07 Accepted:2026-01-28 Online:2026-08-29 Published:2026-08-22
Contact: Christian W. Gruber,E-mail:christian.w.gruber@meduniwien.ac.at
Supported by:
This project was funded by the Austrian Science Fund (FWF) projects ZK-81B (https://doi.org/10.55776/ZK81), PIN5093924 (https://doi.org/10.55776/PIN5093924) and P36736-B (DOI:10.0.217.224/P36736). CWG and RH were additionally supported by the OeAD Austrian-African Research Network Africa-UniNet (P137). MM was supported by an Australian Research Council Future Fellowship (FT210100266).

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

Roland Hellinger¹, Paula Schwarz¹, Jonathan Dieringer¹, Carina Ebermann¹, Kirtikumar B. Jadhav², Markus Muttenthaler^2,3, Christian W. Gruber¹

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

通讯作者: Christian W. Gruber,E-mail:christian.w.gruber@meduniwien.ac.at
基金资助:
This project was funded by the Austrian Science Fund (FWF) projects ZK-81B (https://doi.org/10.55776/ZK81), PIN5093924 (https://doi.org/10.55776/PIN5093924) and P36736-B (DOI:10.0.217.224/P36736). CWG and RH were additionally supported by the OeAD Austrian-African Research Network Africa-UniNet (P137). MM was supported by an Australian Research Council Future Fellowship (FT210100266).

Abstract

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 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.

Key words: Prolyl oligopeptidase, Plant peptide discovery, Peptide-protease inhibition, Cystine-knot peptide, Cyclotide, Peptidomics

摘要： 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.

关键词: Prolyl oligopeptidase, Plant peptide discovery, Peptide-protease inhibition, Cystine-knot peptide, Cyclotide, Peptidomics

Roland Hellinger, Paula Schwarz, Jonathan Dieringer, Carina Ebermann, Kirtikumar B. Jadhav, Markus Muttenthaler, Christian W. Gruber. Tropical psychotria plants are a rich source for peptide inhibitors of human prolyl oligopeptidase[J]. Natural Products and Bioprospecting, 2026, 16(4): 54-54.

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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

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