title: Inhibition of Human Prolyl Oligopeptidase Activity by the Cyclotide Psysol 2 Isolated from Psychotria solitudinum.
abstract: Cyclotides are head-to-tail cyclized peptides comprising a stabilizing cystine-knot motif. To date, they are well known for their diverse bioactivities such as anti-HIV and immunosuppressive properties. Yet little is known about specific molecular mechanisms, in particular the interaction of cyclotides with cellular protein targets. Native and synthetic cyclotide-like peptides from Momordica plants are potent and selective inhibitors of different serine-type proteinases such as trypsin, chymotrypsin, matriptase, and tryptase-beta. This study describes the bioactivity-guided isolation of a cyclotide from Psychotria solitudinum as an inhibitor of another serine-type protease, namely, the human prolyl oligopeptidase (POP). Analysis of the inhibitory potency of Psychotria extracts and subsequent fractionation by liquid chromatography yielded the isolated peptide psysol 2 (1), which exhibited an IC50 of 25 μM. In addition the prototypical cyclotide kalata B1 inhibited POP activity with an IC50 of 5.6 μM. The inhibitory activity appeared to be selective for POP, since neither psysol 2 nor kalata B1 were able to inhibit the proteolytic activity of trypsin or chymotrypsin. The enzyme POP is well known for its role in memory and learning processes, and it is currently being considered as a promising therapeutic target for the cognitive deficits associated with several psychiatric and neurodegenerative diseases, such as schizophrenia and Parkinson's disease. In the context of discovery and development of POP inhibitors with beneficial ADME properties, cyclotides may be suitable starting points considering their stability in biological fluids and possible oral bioavailability.
authors.affiliation: †Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Hellinger
authors.affiliation: †Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Koehbach
authors.affiliation: ‡Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Puigpinós
authors.affiliation: ⊥School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Clark
authors.affiliation: ‡Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tarragó
authors.affiliation: ‡Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.|∥Department of Organic Chemistry, University of Barcelona (UB), 08028 Barcelona, Spain.
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
authors.affiliation: †Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Gruber
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D002918:Chymotrypsin / Q000187:drug effects; D047169:Cyclotides / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D000085822:Prolyl Oligopeptidases; D032069:Psychotria / Q000737:chemistry*; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000187:drug effects
chemical_list: D047169:Cyclotides; D015842:Serine Proteinase Inhibitors; C091930:kalata B1; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D014357:Trypsin