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Published on: February 16, 2015
Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality
1Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Abstract:
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.
Insights
Selective inhibitors targeting caspases 3 and 7 effectively block apoptosis, preserving cell function. This finding suggests a novel therapeutic strategy for conditions like osteoarthritis, characterized by excessive programmed cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Caspases are crucial proteases involved in programmed cell death (apoptosis).
- A key question is whether inhibiting specific effector caspases can prevent cell death.
Purpose of the Study:
- To identify and characterize selective non-peptide inhibitors of effector caspases 3 and 7.
- To demonstrate the efficacy of these inhibitors in preventing apoptosis and maintaining cell functionality.
- To elucidate the structural basis for the selectivity of novel inhibitors.
Main Methods:
- Identification of potent and selective non-peptide inhibitors for caspases 3 and 7.
- X-ray crystallography to determine the co-crystal structure of caspase 3 with an isatin sulfonamide inhibitor.
- Assays to assess apoptosis inhibition and cell functionality (e.g., type II collagen promoter activity) in neutrophils and chondrocytes.
Main Results:
- Novel isatin sulfonamide inhibitors selectively target caspases 3 and 7.
- These inhibitors block apoptosis in murine neutrophils and human chondrocytes.
- Structural analysis reveals selectivity is achieved through interaction with the S(2) subsite, not the S(1) pocket.
- Cellular function, including type II collagen promoter activity, is maintained in inhibited chondrocytes.
Conclusions:
- Selective inhibition of caspases 3 and 7 is sufficient to block apoptosis.
- Isatin sulfonamide inhibitors offer a promising therapeutic avenue for diseases involving excessive apoptosis, such as osteoarthritis.
- Maintaining chondrocyte function through caspase inhibition could be key for cartilage homeostasis.
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