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Selective Inhibition of the Immunoproteasome by Ligand-Induced Crosslinking of the Active Site

Dubiella, Christian ; Cui, Haissi ; Gersch, Malte ; Brouwer, Arwin J. ; Sieber, Stephan A. ; Krüger, Achim ; Liskamp, Rob M. J. ; Groll, Michael

Angewandte Chemie (International ed.), 2014-10, Vol.53 (44), p.11969-11973 [Periódico revisado por pares]

Weinheim: WILEY-VCH Verlag

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  • Título:
    Selective Inhibition of the Immunoproteasome by Ligand-Induced Crosslinking of the Active Site
  • Autor: Dubiella, Christian ; Cui, Haissi ; Gersch, Malte ; Brouwer, Arwin J. ; Sieber, Stephan A. ; Krüger, Achim ; Liskamp, Rob M. J. ; Groll, Michael
  • Assuntos: Blockage ; Catalysis ; Crosslinking ; Disorders ; Drug Design ; Fluorides ; immunoproteasome ; Inhibition ; Inhibitors ; Inversions ; Ligands ; Medical services ; peptido sulfonyl fluoride ; Proteasome Endopeptidase Complex - chemistry ; Proteasome Inhibitors - chemistry ; umpolung
  • É parte de: Angewandte Chemie (International ed.), 2014-10, Vol.53 (44), p.11969-11973
  • Notas: This work was funded by SFB 1035A2 and DFG GR 1861/10-1. We thank R. Feicht, R. Baur, and A. Späth for assistance with the experiments and the staff of PXI of Paul Scherrer Institute, Swiss Light Source (Villigen, Switzerland) for help with data collection.
    istex:8D255D311BEBB0923718CC58A99187F7873404C5
    ark:/67375/WNG-0T69RJ73-6
    DFG - No. GR 1861/10-1
    ArticleID:ANIE201406964
    This work was funded by SFB 1035A2 and DFG GR 1861/10‐1. We thank R. Feicht, R. Baur, and A. Späth for assistance with the experiments and the staff of PXI of Paul Scherrer Institute, Swiss Light Source (Villigen, Switzerland) for help with data collection.
    ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: The concept of proteasome inhibition ranks among the latest achievements in the treatment of blood cancer and represents a promising strategy for modulating autoimmune diseases. In this study, we describe peptidic sulfonyl fluoride inhibitors that selectively block the catalytic β5 subunit of the immunoproteasome by inducing only marginal cytotoxic effects. Structural and mass spectrometric analyses revealed a novel reaction mechanism involving polarity inversion and irreversible crosslinking of the proteasomal active site. We thus identified the sulfonyl fluoride headgroup for the development and optimization of immunoproteasome selective compounds and their possible application in autoimmune disorders. The current benchmark for proteasome inhibition, immunoproteasome inhibitors featuring α′,β′‐epoxyketones, were compared to peptido sulfonyl fluorides (PSF) in terms of their mechanism of action, selectivity, and cytotoxicity. PSFs were found to remove the catalytically active nucleophile and then crosslink the active site. Cell‐based activity and viability assays designate this warhead for selective immunoproteasome blockage.
  • Editor: Weinheim: WILEY-VCH Verlag
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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