A class of allosteric caspase inhibitors identified by high-throughput screening Journal Article
| Authors: | Feldman, T.; Kabaleeswaran, V.; Jang, S. B.; Antczak, C.; Djaballah, H.; Wu, H.; Jiang, X. |
| Article Title: | A class of allosteric caspase inhibitors identified by high-throughput screening |
| Abstract: | Caspase inhibition is a promising approach for treating multiple diseases. Using a reconstituted assay and high-throughput screening, we identified a group of nonpeptide caspase inhibitors. These inhibitors share common chemical scaffolds, suggesting the same mechanism of action. They can inhibit apoptosis in various cell types induced by multiple stimuli; they can also inhibit caspase-1-mediated interleukin generation in macrophages, indicating potential anti-inflammatory application. While these compounds inhibit all the tested caspases, kinetic analysis indicates they do not compete for the catalytic sites of the enzymes. The cocrystal structure of one of these compounds with caspase-7 reveals that it binds to the dimerization interface of the caspase, another common structural element shared by all active caspases. Consistently, biochemical analysis demonstrates that the compound abates caspase-8 dimerization. Based on these kinetic, biochemical, and structural analyses, we suggest that these compounds are allosteric caspase inhibitors that function through binding to the dimerization interface of caspases. © 2012 Elsevier Inc. |
| Keywords: | unclassified drug; chemical analysis; apoptosis; cell line; enzyme activation; high throughput screening; caspase inhibitor; caspases; high-throughput screening assays; cell type; cytokine; amino acid sequence; molecular sequence data; kinetics; protein multimerization; crystal structure; dimerization; crystallography, x-ray; caspase 8; caspase 9; conformational transition; macrophage; catalytic domain; mutagenesis; interleukins; enzyme active site; interleukin 1beta converting enzyme; cytochrome c; cytochromes c; anti-inflammatory agents; caspase 7; enzyme activator; comp a; comp b; comp c; comp d; caspase inhibitors |
| Journal Title: | Molecular Cell |
| Volume: | 47 |
| Issue: | 4 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2012-08-24 |
| Start Page: | 585 |
| End Page: | 595 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2012.06.007 |
| PROVIDER: | scopus |
| PMCID: | PMC3428514 |
| PUBMED: | 22795132 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 October 2012" - "CODEN: MOCEF" - "Source: Scopus" |
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