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Caspases are a complex group of enzymes that bring about apoptosis, also known as programmed cell death. A natural group of caspase inhibitor enzymes are activated by the cleavage of an additional class of caspases. Another type of inhibitor found naturally is that of viruses who use them as part of their infection process. Researchers often use caspase inhibitors in studies of cell biology and biochemistry to try and inhibit one particular type of caspase to see the effects on cell death in the absence of its activity. Such inhibitors are also of interest as potential clinical drugs.
The tremendous importance of caspases has made them the target of an immense amount of research in biochemistry and cell biology. It is a very common approach in enzymology to use an inhibitor against a particular enzyme and then look for changes once the enzyme being studied no longer has activity. Some inhibitors are obtained from natural sources, while others are specifically designed to target the specific enzymes. There is a wide array of apoptosis inhibitors commercially available.
Many natural enzyme inhibitors are short chains of amino acids, known as peptides. The field of peptidomimetics allows the synthesis of compounds that are structurally similar to natural peptides, but also have unusual features. A group of caspase inhibitors has a sequence that is cleaved by particular caspases. It is coupled to a fluorescent tag, so the enzyme’s activity can be detected when the particular caspase is active.
Using such assays, it had been thought that groups of caspase inhibitors were specific for the individual forms of caspases being studied. Detailed research utilizing these inhibitors found that many of the compounds were not as specific as previously thought. At the concentrations used in assays in cell biology experiments, other forms of caspases that were not the target enzyme were also found to be inhibited. Research indicating effects thought to be due to a specific caspase had to be reevaluated.
A number of different caspase inhibitors have been tested in clinical trials for a variety of conditions. Results have been promising when people with liver damage have been treated with such an inhibitor, and it has delayed the death of liver cells. Another example is that of patients who had suffered the cutoff of oxygen and blood to the brain. Experimental usage of a caspase inhibitor was found to help prevent tissue damage in such cases.
Programmed cell death can be a defense mechanism to kill cells rather than have them be infected by microorganisms. Certain types of viruses, such as the cowpoxes, use caspase inhibitors to prevent the target cells from undergoing apoptosis. This enables them to successfully invade the cells.
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