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

Angewandte Chemie International Edition, 2014, DOI: 10.1002/anie.201406964, Volume 53, Issue 44, pages 11969–11973, published on 22.09.2014
Angewandte Chemie International Edition, online article
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.  

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