Controlling apoptosis by inhibition of caspases.
The intracellular cysteine proteinases grouped under the common name of caspases are important participants in the process of programmed cell death called apoptosis. Of the nearly fourteen mammalian members discovered thus far caspase 1 or (interleukin 1beta converting enzyme; ICE), and possibly other related family members also serve as activator of cytokines. In general, caspases act on a number of cellular targets including other caspase family members leading ultimately to apopto4 4is through a highly integrated and regulated biological, biochemical and genetic mechanism. The proper execution of apoptosis is crucial during developmental stages and continues to be of critical importance for the well being of the mature organism. However, in a number of degenerative diseases the pathological states are characterized by an exacerbated loss of certain types of cells, cellular death that has morphological characteristics of apoptosis. Fortunately, it has been known for sometime that induced apoptosis that proceeds through the activation of caspases can be inhibited to rescue these cells and allow them to remain viable. This realization has attracted attention towards caspases as likely targets for pharmacological intervention, believing that inhibition of their enzymatic activity in the compromised cells will prevent the unwanted high rate of cellular death. Here we survey natural and synthetic inhibitors of caspases that have been reported to date, including some commonly used peptide inhibitors that serve as "tool reagents" in research and others that have been used to map inhibitor binding interaction in the active site.
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Department of Structural Biology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, Mail Code UE0447, King of Prussia, PA 19406, USA.
Abdel-Meguid
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D020169:Caspases