title: Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site.
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.
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany).
authors.forename: Christian
authors.initials: C
authors.lastname: Dubiella
authors.forename: Haissi
authors.initials: H
authors.lastname: Cui
authors.forename: Malte
authors.initials: M
authors.lastname: Gersch
authors.forename: Arwin J
authors.initials: AJ
authors.lastname: Brouwer
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
mesh_terms: D015195:Drug Design; D008024:Ligands; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D061988:Proteasome Inhibitors / Q000737:chemistry*
chemical_list: D008024:Ligands; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: drug design; immunoproteasome; inhibitors; peptido sulfonyl fluoride; umpolung