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Angew Chem Int Ed Engl. 2014 Oct 27;53(44):11969-73. doi: 10.1002/anie.201406964. Epub 2014 Sep 22.

Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site.

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  • 1Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany).


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.

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


drug design; immunoproteasome; inhibitors; peptido sulfonyl fluoride; umpolung

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