Selective Inhibition of the Immunoproteasome by Ligand-Induced Crosslinking of the Active Site

被引：74

作者：

Dubiella, Christian ^{[1
]}

Cui, Haissi ^{[3
]}

Gersch, Malte ^{[1
]}

Brouwer, Arwin J. ^{[4
]}

Sieber, Stephan A. ^{[1
]}

Krueger, Achim ^{[3
]}

Liskamp, Rob M. J. ^{[2
]}

Groll, Michael ^{[1
]}

机构：

[1] Tech Univ Munich, Dept Chem, CIPSM, D-85747 Garching, Germany

[2] Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland

[3] Tech Univ Munich, Inst Expt Oncol & Therapy Res, D-81675 Munich, Germany

[4] Univ Utrecht, NL-3508 TB Utrecht, Netherlands

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2014年 / 53卷 / 44期

关键词：

drug design; inhibitors; immunoproteasome; peptido sulfonyl fluoride; umpolung; PROTEASOME INHIBITORS; SPECIFICITY; RESISTANCE;

D O I：

10.1002/anie.201406964

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 beta 5 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.

引用

页码：11969 / 11973

页数：5

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