Potent and Selective Nonpeptide Inhibitors of Caspases 3 and 7 Inhibit Apoptosis and Maintain Cell Functionality
| Autor: | Michael W. Lark, Christine Debouck, Kalindi Vaidya, Mark E. Nuttall, Kyung O. Johanson, James D. Winkler, Alison M. Badger, Martha S. Head, Paul M. Keller, Mark Alan Levy, R. Curtis Haltiwanger, Larry J. Suva, Cheryl A. Janson, Sherin S. Abdel-Meguid, Po-Huang Liang, Patrick McDevitt, George K. Chan, Nestor O. Concha, Daniel P. Nadeau, Kristine Kikly, Dennis Lee, Scott A. Long, Winnie Chan, Walter E. DeWolf, Ryan M Dominic, Susan B. Richardson, Maxine Gowen, Thaddeus A. Tomaszek, Terry A. Francis, Chiu-Mei Sung, Jerry L. Adams |
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| Rok vydání: | 2000 |
| Předmět: |
Isatin
Models Molecular Programmed cell death Neutrophils Apoptosis Caspase 3 Crystallography X-Ray Biochemistry Caspase 7 Amino Acid Chloromethyl Ketones Mice Chondrocytes Osteoarthritis Animals Humans Enzyme Inhibitors Promoter Regions Genetic Molecular Biology Caspase Sulfonamides Binding Sites Molecular Structure biology NLRP1 Intrinsic apoptosis Cell Biology Caspase Inhibitors Recombinant Proteins Cell biology XIAP biology.protein Camptothecin Collagen |
| Zdroj: | Journal of Biological Chemistry. 275:16007-16014 |
| ISSN: | 0021-9258 |
| Popis: | Caspases have been strongly implicated to play an essential role in apoptosis. A critical question regarding the role(s) of these proteases is whether selective inhibition of an effector caspase(s) will prevent cell death. We have identified potent and selective non-peptide inhibitors of the effector caspases 3 and 7. The inhibition of apoptosis and maintenance of cell functionality with a caspase 3/7-selective inhibitor is demonstrated for the first time, and suggests that targeting these two caspases alone is sufficient for blocking apoptosis. Furthermore, an x-ray co-crystal structure of the complex between recombinant human caspase 3 and an isatin sulfonamide inhibitor has been solved to 2.8-A resolution. In contrast to previously reported peptide-based caspase inhibitors, the isatin sulfonamides derive their selectivity for caspases 3 and 7 by interacting primarily with the S(2) subsite, and do not bind in the caspase primary aspartic acid binding pocket (S(1)). These inhibitors blocked apoptosis in murine bone marrow neutrophils and human chondrocytes. Furthermore, in camptothecin-induced chondrocyte apoptosis, cell functionality as measured by type II collagen promoter activity is maintained, an activity considered essential for cartilage homeostasis. These data suggest that inhibiting chondrocyte cell death with a caspase 3/7-selective inhibitor may provide a novel therapeutic approach for the prevention and treatment of osteoarthritis, or other disease states characterized by excessive apoptosis. |
| Databáze: | OpenAIRE |
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