Prolyl oligopeptidase is a cytosolic serine peptidase that hydrolyses proline-containing peptides at the carboxy terminus of proline residues. It has been associated with schizophrenia, bipolar affective disorder, and related neuropsychiatric disorders and therefore may have important clinical implications. Thirty-one isoquinoline alkaloids of various structural types, previously isolated in our laboratory, were screened for their ability to inhibit prolyl oligopeptidase. Promising results have been showed by alkaloids californidine (IC50=55.6±3.5 μM), dihydrosanquinarine (IC50=99.1±7.6 μM), corypalmine (IC50=128.0±10.5 μM) and N-methyllaurotetanine (IC50=135.0±11.7 μM).

• Klíčová slova
• Argemonine (CID: 442168), Berberine (PubChem CID: 2353), Californidine, Californidine (PubChem CID: 45266443), Canadine (PubChem CID: 443422), Corynoline (PubChem CID: 177014), Corypalmine (PubChem CID: 185605), Dihydrosanquinarine, Dihydrosanquinarine (PubChem CID: 124069), Isoquinoline alkaloids, N-Methyllaurotetanine (PubChem CID: 16573), Prolyl oligopeptidase,
• MeSH
• alkaloidy chemie   MeSH
• aporfiny chemie   MeSH
• dioxoly chemie   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   MeSH
• inhibitory serinových proteinas chemie   MeSH
• isochinoliny chemie   MeSH
• molekulární struktura MeSH
• prolyloligopeptidasy MeSH
• serinové endopeptidasy chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alkaloidy MeSH
• aporfiny MeSH
• californidine MeSH Prohlížeč
• corypalmine MeSH Prohlížeč
• dioxoly MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• inhibitory serinových proteinas MeSH
• isochinoliny MeSH
• N-methyllaurotetanine MeSH Prohlížeč
• prolyloligopeptidasy MeSH
• serinové endopeptidasy MeSH

Prolyl oligopeptidase (POP), also called prolyl endopeptidase, is a cytosolic enzyme investigated by several research groups. It has been proposed to play an important role in physiological processes such as modulation of the levels of several neuronal peptides and hormones containing a proline residue. Due to its proteolytic activity and physiological role in cell signaling pathways, inhibition of POP offers an emerging approach for the treatment of Alzheimer's and Parkinson's diseases as well as other diseases related to cognitive impairment. Furthermore, it may also represent an interesting target for treatment of neuropsychiatric disorders, and as an antiangiogenesis or antineoplastic agent. In this review paper, we summarized naturally occurring POP inhibitors together with peptide-like inhibitors and their biological effects. Some of them have shown promising results and interesting pharmacological profiles. However, to date, there is no POP inhibitor available on the market although several clinical trials have been undertaken.

• Klíčová slova
• antineoplastic effect, cognition-enhancer, naturally occurring POP inhibitors, neuropsychiatric disorders, prolyl oligopeptidase, prolyl oligopeptidase inhibitors, synthetic POP inhibitors,
• MeSH
• inhibitory serinových proteinas chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• prolyloligopeptidasy MeSH
• serinové endopeptidasy metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory serinových proteinas MeSH
• PREPL protein, human MeSH Prohlížeč
• prolyloligopeptidasy MeSH
• serinové endopeptidasy MeSH

Eleven Amaryllidaceae alkaloids (1-11) were isolated from fresh bulbs of Chlidanthus fragrans Herb. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic experiments. Complete NMR assignments were achieved for deoxypretazzetine (1). All compounds were evaluated for their erythrocytic acetylcholinesterase and serum butyrylcholinesterase inhibition activity using Ellman's method. In the prolyl oligopeptidase assay, Z-Gly-Pro-p-nitroanilide was used as substrate. In biological assays, only the crinine type Amaryllidaceae alkaloid undulatine showed promising acetylcholinesterase and prolyl oligopeptidase inhibition activity with IC50 values of 23.0 +/- 1.0 microM and 1.96 +/- 0.12 mM, respectively. Other isolated compounds were considered inactive.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• alkaloidy amarylkovitých chemie   izolace a purifikace   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• liliovité chemie   enzymologie   MeSH
• magnetická rezonanční spektroskopie MeSH
• prolyloligopeptidasy MeSH
• serinové endopeptidasy metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• alkaloidy amarylkovitých MeSH
• butyrylcholinesterasa MeSH
• prolyloligopeptidasy MeSH
• serinové endopeptidasy MeSH

Alzheimer's disease is an age-related, neurodegenerative disorder, characterized by cognitive impairment and restrictions in activities of daily living. This disease is the most common form of dementia with complex multifactorial pathological mechanisms. Many therapeutic approaches have been proposed. Among them, inhibition of acetylcholinesterase, butyrylcholinesterase, and prolyl oligopeptidase can be beneficial targets in the treatment of Alzheimer's disease. Roots, along with aerial parts of Argemone platyceras, were extracted with ethanol and fractionated on an alumina column using light petrol, chloroform and ethanol. Subsequently, repeated preparative thin-layer chromatography led to the isolation of (+)-laudanosine, protopine, (-)-argemonine, allocryptopine, (-)-platycerine, (-)-munitagine, and (-)-norargemonine belonging to pavine, protopine and benzyltetrahydroisoquinoline structural types. Chemical structures of the isolated alkaloids were elucidated by optical rotation, spectroscopic and spectrometric analysis (NMR, MS), and comparison with literature data. (+)-Laudanosine was isolated from A. platyceras for the first time. Isolated compounds were tested for human blood acetylcholinesterase, human plasma butyrylcholinesterase and recombinant prolyl oligopeptidase inhibitory activity. The alkaloids inhibited the enzymes in a dose-dependent manner. The most active compound (-)-munitagine, a pavine alkaloid, inhibited both acetylcholinesterase and prolyl oligopeptidase with IC50 values of 62.3 ± 5.8 µM and 277.0 ± 31.3 µM, respectively.

• Klíčová slova
• Alzheimer’s disease, Argemone platyceras, acetylcholinesterase, alkaloids, butyrylcholinesterase, prolyl oligopeptidase,
• MeSH
• alkaloidy chemie   izolace a purifikace   farmakologie   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• Argemone chemie   MeSH
• butyrylcholinesterasa účinky léků   MeSH
• cholinesterasy účinky léků   MeSH
• chromatografie na tenké vrstvě metody   MeSH
• enzymatické testy metody   MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• kořeny rostlin chemie   MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie metody   MeSH
• objevování léků MeSH
• prolyloligopeptidasy MeSH
• rostlinné extrakty chemie   MeSH
• serinové endopeptidasy účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy MeSH
• butyrylcholinesterasa MeSH
• cholinesterasy MeSH
• inhibitory enzymů MeSH
• PREPL protein, human MeSH Prohlížeč
• prolyloligopeptidasy MeSH
• rostlinné extrakty MeSH
• serinové endopeptidasy MeSH

Berberine, a naturally occurring compound, possesses an interesting multipotent pharmacological profile potentially applicable for Alzheimer's disease (AD) treatment. In this study, a series of novel 22 berberine derivatives was developed and tested in vitro. Berberine core was substituted at position 9-O of its aromatic ring region. All the hybrids under the study revealed multi-targeted profile inhibiting prolyl oligopeptidase, acetylcholinesterase and butyrylcholinesterase highlighting 4a, 4g, 4j, 4l and 4s possessing balanced activities in the micromolar range. The top-ranked candidates in terms of the most pronounced potency against POP, AChE and BChE can be classified as 4d, 4u and 4v, bearing 4-methylbenzyl, (naphthalen-2-yl)methylene and 1-phenoxyethyl moieties, respectively. In vitro data were corroborated by detailed kinetic analysis of the selected lead molecules. 4d, 4u and 4v were also inspected for their potential to inhibit aggregation of two abberant proteins in AD, namely amyloid beta and tau, indicating their potential disease-modifying properties. To explain the results of our study, we carried out docking simulation to the active sites of the respective enzyme with the best berberine derivatives, along with QSAR study. We also investigated compounds' potential permeability through blood-brain barrier by applying parallel artificial membrane permeation assay and addressed their cytotoxicity profile.

• Klíčová slova
• Acetylcholinesterase, Alzheimer’s disease, Amyloid beta, Butyrylcholinesterase, In silico, Multi-target directed ligands, Prolyl oligopeptidase, Quantitative structure-activity relationship, Tau protein,
• MeSH
• berberin chemie   metabolismus   farmakologie   MeSH
• cholinesterasové inhibitory chemie   metabolismus   farmakologie   MeSH
• cholinesterasy metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• prolyloligopeptidasy antagonisté a inhibitory   MeSH
• racionální návrh léčiv * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• berberin MeSH
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH
• prolyloligopeptidasy MeSH

BACKGROUND: Blood flukes of the genus Schistosoma cause schistosomiasis, a parasitic disease that infects over 240 million people worldwide, and for which there is a need to identify new targets for chemotherapeutic interventions. Our research is focused on Schistosoma mansoni prolyl oligopeptidase (SmPOP) from the serine peptidase family S9, which has not been investigated in detail in trematodes. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that SmPOP is expressed in adult worms and schistosomula in an enzymatically active form. By immunofluorescence microscopy, SmPOP is localized in the tegument and parenchyma of both developmental stages. Recombinant SmPOP was produced in Escherichia coli and its active site specificity investigated using synthetic substrate and inhibitor libraries, and by homology modeling. SmPOP is a true oligopeptidase that hydrolyzes peptide (but not protein) substrates with a strict specificity for Pro at P1. The inhibition profile is analogous to those for mammalian POPs. Both the recombinant enzyme and live worms cleave host vasoregulatory, proline-containing hormones such as angiotensin I and bradykinin. Finally, we designed nanomolar inhibitors of SmPOP that induce deleterious phenotypes in cultured schistosomes. CONCLUSIONS/SIGNIFICANCE: We provide the first localization and functional analysis of SmPOP together with chemical tools for measuring its activity. We briefly discuss the notion that SmPOP, operating at the host-parasite interface to cleave host bioactive peptides, may contribute to the survival of the parasite. If substantiated, SmPOP could be a new target for the development of anti-schistosomal drugs.

• MeSH
• DNA primery genetika   MeSH
• Escherichia coli MeSH
• fluorescenční mikroskopie MeSH
• hydrolýza MeSH
• imunoblotting MeSH
• katalytická doména genetika   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• molekulární modely * MeSH
• prolyloligopeptidasy MeSH
• regulace genové exprese enzymů fyziologie   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• Schistosoma mansoni enzymologie   MeSH
• serinové endopeptidasy genetika   metabolismus   MeSH
• stanovení celkové genové exprese MeSH
• substrátová specifita MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA primery MeSH
• prolyloligopeptidasy MeSH
• rekombinantní proteiny MeSH
• serinové endopeptidasy MeSH

Peptidomimetic inhibitors of fibroblast activation protein (FAP) are regarded as promising tools for tumor targeting in vivo. Even though several peptidomimetic compounds with nanomolar potency have been described, broad chemical space for further modification remained unexplored. Therefore, we set to analyze the structure-activity relationship (SAR) of pseudopeptide compound series with α-ketoamide warheads in order to explore the contributions of the P1' and P2' moieties to the inhibitory potency. A series of novel inhibitors bearing varied P1' and/or P2' moieties was synthesized by combining a Passerini reaction-Amine Deprotection-Acyl Migration (PADAM) approach with peptide coupling and subsequent oxidation. The resulting compounds inhibited FAP and the related prolyl endopeptidase (PREP) with potencies in the nanomolar to sub-nanomolar range. The most potent FAP inhibitor IOCB22-AP446 (6d, IC50 = 89 pM) had about 36-fold higher inhibition potency than the most potent inhibitor published to date. The compounds were selective over FAP's closest homolog DPP-IV, were stable in human and mouse plasma and in mouse microsomes, and displayed minimal cytotoxicity in tissue cultures.

• Klíčová slova
• FAP inhibitor, Fibroblast activation protein, Prolyl endopeptidase, Seprase, Serine protease inhibition, α-Ketoamide inhibitor,
• MeSH
• fibroblasty metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• myši MeSH
• prolyloligopeptidasy metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• prolyloligopeptidasy MeSH

An acidic prolyl endoprotease from Aspergillus niger was isolated from the commercial product Brewers Clarex to evaluate its possible application in proteomics. The chromatographic purification yielded a single protein band in sodium dodecyl sulfate polyacrylamide gel electrophoresis providing an apparent molecular mass of 63 kDa and a broad peak (m/z 58,061) in linear matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) indicating the glycoprotein nature of the enzyme. Indeed, a colorimetric assessment with phenol and sulfuric acid showed the presence of neutral sugars (9% of weight). The subsequent treatment with N-glycosidase F released a variety of high-mannose type N-glycans, which were successfully detected using MALDI-TOF MS. MALDI-TOF/TOF tandem MS analysis of glycopeptides from a tryptic digest of prolyl endoprotease unraveled the identity of the N-glycosylation site in the primary structure. The data obtained also show that the enzyme is present in its processed form, i.e. without putative signal and propeptide parts. Spectrophotometric measurements demonstrated optimal activity at pH 4.0-4.5 and also high thermostability for the cleavage at the C-terminal part of proline residues. In-solution digestion of standard proteins (12-200 kDa) allowed to evaluate the cleavage specificity. The enzyme acts upon proline and alanine residues, but there is an additional minor cleavage at some other residues like Gly, Leu, Arg, Ser and Tyr. The digestion of a honeybee peptide comprising six proline residues (apidaecin 1A) led to the detection of specific peptides terminated by proline as it was confirmed by MALDI postsource decay analysis.

• MeSH
• Aspergillus niger enzymologie   MeSH
• autolýza MeSH
• fungální proteiny chemie   izolace a purifikace   metabolismus   MeSH
• glykosylace MeSH
• koncentrace vodíkových iontů MeSH
• molekulární sekvence - údaje MeSH
• peptidové fragmenty chemie   metabolismus   MeSH
• polysacharidy chemie   metabolismus   MeSH
• prolyloligopeptidasy MeSH
• proteiny chemie   metabolismus   MeSH
• proteomika metody   MeSH
• sekvence aminokyselin MeSH
• serinové endopeptidasy chemie   izolace a purifikace   metabolismus   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fungální proteiny MeSH
• peptidové fragmenty MeSH
• polysacharidy MeSH
• prolyloligopeptidasy MeSH
• proteiny MeSH
• serinové endopeptidasy MeSH

• Publikační typ
• časopisecké články MeSH

The activities of dipeptidyl peptidase IV (DPP-IV), prolyl endopeptidase (PE) and cathepsin B (CB) were investigated in primary human lung tumours and matched lung parenchyma, using continuous-rate fluorometric assays of the enzymes. Squamous-cell lung carcinomas showed significantly higher specific activities of all three enzymes studied. In lung adenocarcinomas only activities of PE and CB were increased significantly. In a limited number of primary human lung tumours of other histological types the activities of DPP-IV, PE and CB were also elevated. Mixing the matched homogenates of lung tumours and lung parenchyma gave additive activities for each enzyme studied. A significant correlation between tumour/lung ratios of specific activities of DPP-IV and CB was observed.

• MeSH
• adenokarcinom enzymologie   MeSH
• dipeptidylpeptidasa 4 MeSH
• dipeptidylpeptidasy a tripeptidylpeptidasy metabolismus   MeSH
• dospělí MeSH
• endopeptidasy metabolismus   MeSH
• fluorometrie MeSH
• kathepsin B metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory plic enzymologie   chirurgie   MeSH
• plíce enzymologie   MeSH
• prolyloligopeptidasy MeSH
• senioři MeSH
• serinové endopeptidasy * MeSH
• spinocelulární karcinom enzymologie   MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• dipeptidylpeptidasa 4 MeSH
• dipeptidylpeptidasy a tripeptidylpeptidasy MeSH
• endopeptidasy MeSH
• kathepsin B MeSH
• PREPL protein, human MeSH Prohlížeč
• prolyloligopeptidasy MeSH
• serinové endopeptidasy * MeSH