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

Dubiella, C., Cui, H., Gersch, M., Brouwer, A. J., Sieber, S. A., Krüger, A., Liskamp, R. M.J. and Groll, M. (2014) Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site. Angewandte Chemie (International Edition), 53(44), pp. 11969-11973. (doi: 10.1002/anie.201406964) (PMID:25244435)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Liskamp, Professor Robert
• Authors: Dubiella, C., Cui, H., Gersch, M., Brouwer, A. J., Sieber, S. A., Krüger, A., Liskamp, R. M.J., and Groll, M.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Angewandte Chemie (International Edition)
• Journal Abbr.: Angew Chem Int Ed Engl
• Publisher: Wiley - V C H Verlag GmbH & Co. KGaA
• ISSN: 1433-7851
• ISSN (Online): 1521-3773