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To study the role of various caspases during apoptosis, we have designed a series of caspase inhibitors based on the cowpox virus cytokine response modifier A (crmA) protein. Wild-type crmA inhibits caspases 1 and 8 and thereby protects cells from apoptosis triggered by ligation of CD95 or tumour necrosis factor (TNF) receptors, but it does not protect against death mediated by other caspases. By replacing the tetrapeptide pseudosubstrate region of crmA (LVAD) with tetrapeptides that are optimal substrates for the different families of caspases, or with the four residues from the cleavage site of the baculovirus protein p35 (DQMD), we have generated a family of caspase inhibitors that show altered ability to protect against cell death. Although DEVD is the optimal substrate for caspase 3, crmA DEVD was degraded rapidly and was a weaker inhibitor than crmA DQMD, which was not degraded. Unlike wild-type crmA and crmA DEVD, crmA DQMD was able to inhibit apoptosis caused by direct activation of caspase 3 and protected lymphoid cells from death induced by radiation and dexamethasone. Significantly, the protected cells were capable of sustained growth.

Original publication




Journal article



Publication Date





330 - 338


Amino Acid Sequence, Animals, Apoptosis, Base Sequence, Caspase Inhibitors, Caspases, Cell Division, Cell Line, Cell Survival, Cysteine Proteinase Inhibitors, DNA Primers, Dexamethasone, Enzyme Activation, Gamma Rays, Gene Expression, Genetic Variation, Humans, Mice, Oligopeptides, Saccharomyces cerevisiae, Serpins, Substrate Specificity, Transfection, Viral Proteins