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Nonpeptidic Selective Inhibitors of the Chymotrypsin‐Like (β5 i) Subunit of the Immunoproteasome
Author(s) -
Sosič Izidor,
Gobec Martina,
Brus Boris,
Knez Damijan,
Živec Matej,
Konc Janez,
Lešnik Samo,
Ogrizek Mitja,
Obreza Aleš,
Žigon Dušan,
Janežič Dušanka,
MlinaričRaščan Irena,
Gobec Stanislav
Publication year - 2016
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.201600190
Subject(s) - protein subunit , chymotrypsin , chemistry , computational biology , biochemistry , stereochemistry , enzyme , biology , gene , trypsin
Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide‐based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin‐like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell‐based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i‐selective probes for possible application in noncancer diseases related to the immunoproteasome.