期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 55, 期 19, 页码 5745-5748出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201600190
关键词
drug design; immunoproteasome; inhibitors; irreversible inhibition; small-molecule inhibitors
资金
- Slovenian Research Agency
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 (5i) 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 5i 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 5i-selective probes for possible application in noncancer diseases related to the immunoproteasome.
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