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  1. Article ; Online: 5-Aminothiazoles Reveal a New Ligand-Binding Site on Prolyl Oligopeptidase Which is Important for Modulation of Its Protein-Protein Interaction-Derived Functions.

    Pätsi, Henri T / Kilpeläinen, Tommi P / Jumppanen, Mikael / Uhari-Väänänen, Johanna / Wielendaele, Pieter Van / De Lorenzo, Francesca / Cui, Hengjing / Auno, Samuli / Saharinen, Janne / Seppälä, Erin / Sipari, Nina / Savinainen, Juha / De Meester, Ingrid / Lambeir, Anne-Marie / Lahtela-Kakkonen, Maija / Myöhänen, Timo T / Wallén, Erik A A

    Journal of medicinal chemistry

    2024  Volume 67, Issue 7, Page(s) 5421–5436

    Abstract: A series of novel 5-aminothiazole-based ligands for prolyl oligopeptidase (PREP) comprise selective, potent modulators of the protein-protein interaction (PPI)-mediated functions of PREP, although they are only weak inhibitors of the proteolytic activity ...

    Abstract A series of novel 5-aminothiazole-based ligands for prolyl oligopeptidase (PREP) comprise selective, potent modulators of the protein-protein interaction (PPI)-mediated functions of PREP, although they are only weak inhibitors of the proteolytic activity of PREP. The disconnected structure-activity relationships are significantly more pronounced for the 5-aminothiazole-based ligands than for the earlier published 5-aminooxazole-based ligands. Furthermore, the stability of the 5-aminothiazole scaffold allowed exploration of wider substitution patterns than that was possible with the 5-aminooxazole scaffold. The intriguing structure-activity relationships for the modulation of the proteolytic activity and PPI-derived functions of PREP were elaborated by presenting a new binding site for PPI modulating PREP ligands, which was initially discovered using molecular modeling and later confirmed through point mutation studies. Our results suggest that this new binding site on PREP is clearly more important than the active site of PREP for the modulation of its PPI-mediated functions.
    MeSH term(s) Prolyl Oligopeptidases/metabolism ; Serine Endopeptidases/metabolism ; Ligands ; Binding Sites ; Thiazoles
    Chemical Substances Prolyl Oligopeptidases (EC 3.4.21.26) ; 5-aminothiazole ; Serine Endopeptidases (EC 3.4.21.-) ; Ligands ; Thiazoles
    Language English
    Publishing date 2024-03-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c01993
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
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  2. Article ; Online: A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy.

    Eteläinen, Tony S / Silva, M Catarina / Uhari-Väänänen, Johanna K / De Lorenzo, Francesca / Jäntti, Maria H / Cui, Hengjing / Chavero-Pieres, Marta / Kilpeläinen, Tommi / Mechtler, Christina / Svarcbahs, Reinis / Seppälä, Erin / Savinainen, Juha R / Puris, Elena / Fricker, Gert / Gynther, Mikko / Julku, Ulrika H / Huttunen, Henri J / Haggarty, Stephen J / Myöhänen, Timo T

    Science translational medicine

    2023  Volume 15, Issue 691, Page(s) eabq2915

    Abstract: Tauopathies are neurodegenerative diseases that are characterized by accumulation of hyperphosphorylated tau protein, higher-order aggregates, and tau filaments. Protein phosphatase 2A (PP2A) is a major tau dephosphorylating phosphatase, and a decrease ... ...

    Abstract Tauopathies are neurodegenerative diseases that are characterized by accumulation of hyperphosphorylated tau protein, higher-order aggregates, and tau filaments. Protein phosphatase 2A (PP2A) is a major tau dephosphorylating phosphatase, and a decrease in its activity has been demonstrated in tauopathies, including Alzheimer's disease. Prolyl oligopeptidase is a serine protease that is associated with neurodegeneration, and its inhibition normalizes PP2A activity without toxicity under pathological conditions. Here, we assessed whether prolyl oligopeptidase inhibition could protect against tau-mediated toxicity in cellular models in vitro and in the PS19 transgenic mouse model of tauopathy carrying the human tau-P301S mutation. We show that inhibition of prolyl oligopeptidase with the inhibitor KYP-2047 reduced tau aggregation in tau-transfected HEK-293 cells and N2A cells as well as in human iPSC-derived neurons carrying either the P301L or tau-A152T mutation. Treatment with KYP-2047 resulted in increased PP2A activity and activation of autophagic flux in HEK-293 cells and N2A cells and in patient-derived iNeurons, as indicated by changes in autophagosome and autophagy receptor markers; this contributed to clearance of insoluble tau. Furthermore, treatment of PS19 transgenic mice for 1 month with KYP-2047 reduced tau burden in the brain and cerebrospinal fluid and slowed cognitive decline according to several behavioral tests. In addition, a reduction in an oxidative stress marker was seen in mouse brains after KYP-2047 treatment. This study suggests that inhibition of prolyl oligopeptidase could help to ameliorate tau-dependent neurodegeneration.
    MeSH term(s) Mice ; Humans ; Animals ; Prolyl Oligopeptidases ; HEK293 Cells ; Tauopathies/metabolism ; tau Proteins/metabolism ; Mice, Transgenic ; Serine Endopeptidases/metabolism ; Enzyme Inhibitors ; Disease Models, Animal
    Chemical Substances Prolyl Oligopeptidases (EC 3.4.21.26) ; tau Proteins ; Serine Endopeptidases (EC 3.4.21.-) ; Enzyme Inhibitors
    Language English
    Publishing date 2023-04-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.abq2915
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6941: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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