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Selective Inhibition of the Immunoproteasome by Ligand‐Induced Crosslinking of the Active Site
Author(s) -
Dubiella Christian,
Cui Haissi,
Gersch Malte,
Brouwer Arwin J.,
Sieber Stephan A.,
Krüger Achim,
Liskamp Rob M. J.,
Groll Michael
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201406964
Subject(s) - active site , chemistry , sulfonyl , proteasome , ligand (biochemistry) , protein subunit , mechanism (biology) , catalysis , combinatorial chemistry , biochemistry , stereochemistry , biophysics , biology , receptor , organic chemistry , alkyl , gene , philosophy , epistemology
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.