prolyl oligopeptidase inhibitors Dotaz Zobrazit nápovědu
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).
- 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
- serinové endopeptidasy chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
- 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
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.
- MeSH
- inhibitory serinových proteinas chemie farmakologie MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura 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
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.
- 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
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
- 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
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.
- 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
- 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
Thirteen known (1-12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13-15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.
- MeSH
- alkaloidy chemie farmakologie MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- lidé MeSH
- Narcissus chemie MeSH
- simulace molekulového dockingu MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Fifteen Amaryllidaceae alkaloids (1-15) of various structural types were isolated by standard chromatographic methods from fresh bulbs of Narcissus poeticus cv. Pink Parasol. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic analyses, and by comparison with literature data. Narcipavline (5) and narcikachnine (6) are reported here for the first time. In their structure are combined two basic structural types of Amaryllidaceae alkaloids (galanthamine- and galanthindole-structural types), which represent a new structural type of these compounds. Alkaloids isolated in sufficient amounts were evaluated for their human erythrocytic acetylcholinesterase, and human serum butyrylcholinesterase (HuBuChE) inhibition activity using Ellman's method. Z-Gly-Pro-p-nitroanilide was used as substrate in the prolyl oligopeptidase (POP) assay. Untested alkaloids were also screened for their cytotoxic activity against a small panel of human cancer cells, which spanned cell lines from different tissue types. In parallel, MRC-5 human fibroblasts were employed to determine overall toxicity against noncancerous cells. Some compounds were evaluated for their antiprotozoal activity. The newly isolated alkaloid narcipavline (5) showed interesting HuBuChE inhibition activity (IC50 = 24.4 ± 1.2 µM), and norlycoramine (11) demonstrated promising POP inhibition (IC50 = 0.21 ± 0.01 mM).
- MeSH
- alkaloidy chemie izolace a purifikace farmakologie MeSH
- buňky A549 MeSH
- buňky HT-29 MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemie izolace a purifikace farmakologie MeSH
- HeLa buňky MeSH
- inhibitory růstu chemie izolace a purifikace farmakologie MeSH
- Jurkat buňky MeSH
- kořeny rostlin MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- myši MeSH
- Narcissus * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Twenty-one known Amaryllidaceae alkaloids of various structural types and one undescribed alkaloid, named narcimatuline, have been isolated from fresh bulbs of Narcissus pseudonarcissus L. cv. Dutch Master. The chemical structures were elucidated by combination of MS, HRMS, 1D and 2D NMR spectroscopic techniques, and by comparison with literature data. Narcimatuline amalgamates two basic scaffolds of Amaryllidaceae alkaloids in its core, namely galanthamine and galanthindole. All isolated compounds were evaluated for their in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), prolyl oligopeptidase (POP), and glycogen synthase kinase-3β (GSK-3β) inhibitory activities. The most interesting biological profile was demonstrated by newly isolated alkaloid narcimatuline.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- alkaloidy amarylkovitých chemie izolace a purifikace farmakologie MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemie izolace a purifikace farmakologie MeSH
- GSK3B antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- Narcissus chemie MeSH
- neuroprotektivní látky chemie izolace a purifikace farmakologie MeSH
- serinové endopeptidasy metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
