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

Christian Dubiella; Haissi Cui; Malte Gersch; Arwin J. Brouwer; Stephan A. Sieber; Achim Krüger; Rob M.J. Liskamp; Michael Groll

doi:10.1002/anie.201406964

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

Christian Dubiella
, Haissi Cui
, Malte Gersch
, Arwin J. Brouwer
, Stephan A. Sieber
, Achim Krüger
, Rob M.J. Liskamp
, Michael Groll

Center for Integrated Protein Science
Technical University of Munich
the University of Utrecht
University of Glasgow

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

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.

Original language	English
Pages (from-to)	11969-11973
Number of pages	5
Journal	Angewandte Chemie International Edition in English
Volume	53
Issue number	44
DOIs	https://doi.org/10.1002/anie.201406964
State	Published - 27 Oct 2014
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Drug design
Immunoproteasome
Inhibitors
Peptido sulfonyl fluoride
Umpolung

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10.1002/anie.201406964

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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.",

keywords = "Drug design, Immunoproteasome, Inhibitors, Peptido sulfonyl fluoride, Umpolung",

author = "Christian Dubiella and Haissi Cui and Malte Gersch and Brouwer, \{Arwin J.\} and Sieber, \{Stephan A.\} and Achim Kr{\"u}ger and Liskamp, \{Rob M.J.\} and Michael Groll",

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doi = "10.1002/anie.201406964",

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T1 - Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site

AU - Dubiella, Christian

AU - Cui, Haissi

AU - Gersch, Malte

AU - Brouwer, Arwin J.

AU - Sieber, Stephan A.

AU - Krüger, Achim

AU - Liskamp, Rob M.J.

AU - Groll, Michael

PY - 2014/10/27

Y1 - 2014/10/27

N2 - 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.

AB - 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.

KW - Drug design

KW - Immunoproteasome

KW - Inhibitors

KW - Peptido sulfonyl fluoride

KW - Umpolung

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AN - SCOPUS:84915750897

SN - 1433-7851

VL - 53

SP - 11969

EP - 11973

JO - Angewandte Chemie International Edition in English

JF - Angewandte Chemie International Edition in English

IS - 44

ER -

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

Abstract

UN SDGs

Keywords

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