Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 beta (IL-1 beta)-converting enzyme (ICE, caspase-1) processes the IL-1 beta precursor to mature inflammatory cytokine IL-1 beta. ICE has been identified as a unique cysteine protease, which cleaves Asp-X bonds, shows resistance to E-64 (an inhibitor of most cysteine proteases) and has a primary structure that is homologous to CED-3, a protein required for apoptosis (programmed cell death) in the nematode Caenorhabditis elegans, and to mammalian cysteine proteases that initiate and execute apoptosis, e.g., apopain/CPP32/caspase-3. The inhibitors of the ICE/CED-3 family or caspases, as they are called recently, may constitute therapeutic agents for amelioration of inflammatory and apoptosis-associated diseases. The most efficient ICE inhibitors are peptide aldehydes and peptidyl chloro or (acyloxy)methanes. A recent study revealed that both D- and L-Asp are accepted by ICE at the P1 of such inhibitors, and the peptidyl (acyloxy)methane analogues having the beta-homo-aspartyl residue [-NH-CH(CH2COOH)-CH2CO-] are inactive. These findings we reexamined in terms of two issues. (a) ICE's resistance to E-64. Since it was thought to be caused by the enzyme's unique substrate specificity, we prepared substrate-based analogues, which were not inhibitory suggesting significant structural difference between the active centers of ICE and papain-like enzymes. (b) Tolerance for D-stereochemistry at the P1 of these inhibitors. In view of the mechanism of cysteine protease inhibition by peptidyl X-methanes, we thought that this phenomenon should be a general characteristic of cysteine proteases and the hAsp-containing analogues should behave as reversible inhibitors. Here, we analyzed the inhibition of ICE and apopain in comparison with that of papain, thrombin, and trypsin by peptide L/D-alpha-aldehydes and their L-beta-homo-aldehyde [-NH-CH(R)-CH2-CHO] analogues. The following results were found. (1) The peptidyl L-beta-homo-aspartals are potent inhibitors for caspases. (2) The L-beta-homo analogues of peptide aldehyde inhibitors designed for other proteases are not inhibitory. (3) Unlike trypsin and thrombin (serine proteases), papain (cysteine protease) shows tolerance for D-stereochemistry at the P1 site of peptide aldehydes in proportion to the lability of the alpha-hydrogen of the P1-D-residue. The complete tolerance of ICE for P1-D-Asp may arise from this residue's high tendency to epimerization. (4) Reaction of cysteine proteases with peptide aldehyde or peptidyl X-methane inhibitors containing P1-D-residues may include alpha-proton abstraction followed by asymmetric induction leading to P1-L-residue-containing products.
Biopolymers 1999
PMID:Peptidyl beta-homo-aspartals (3-amino-4-carboxybutyraldehydes): new specific inhibitors of caspases. 1038 Mar 58

Human term-placental culture techniques such as villous explant or dual perfusion are commonly used to study trophoblast function under control and experimentally manipulated conditions. We have compared trophoblast viability during perfusion and in explants cultured under various conditions by monitoring glucose consumption, protein synthesis and secretion, expression of differentiation-specific genes, induction of stress proteins and apoptotic cell death. The tissue was obtained from term-placentae of uncomplicated pregnancies after elective Caesarean delivery. We observed a severe loss of trophoblast viability in explants irrespective of the culture conditions used. Over 7 h of culture the amount of the differentiation specific placental hormones hCG, hPL and leptin accumulated in the medium dropped significantly. Analysis of their expression by semi-quantitative and real-time RT-PCR revealed that the down-regulation of expression occurred at the transcriptional level. This transcriptional repression was accompanied by induction of the stress-proteins RTP and BiP/GRP78. Analysis of apoptotic cell death by TUNEL assay and immunohistochemical detection of the caspase-3-specific degradation product of cytokeratin 18 revealed prominent cell death after 7 h of culture. These results are in contrast to the findings obtained in perfused placental tissue where, after 7 h of culture, hormone secretion, expression of stress proteins and cell death were similar as in native tissue. This difference between villous explant incubation and dual perfusion is also reflected by a significantly higher consumption of glucose in perfused tissue.
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PMID:Trophoblast viability in perfused term placental tissue and explant cultures limited to 7-24 hours. 1312 86

Resveratrol is a naturally occurring polyphenolic phytoalexin with chemopreventive properties. We previously reported a synergistic anti-proliferative effect of resveratrol and clofarabine against malignant mesothelioma (MM) cells. Here, we further investigated molecular mechanisms involved in the synergistic interaction of these compounds in MM MSTO-211H cells. Resveratrol, in combination with clofarabine, time-dependently induced a strong cytotoxic effect with the nuclear accumulation of phospho-p53 (p-p53) in MSTO-211H cells, but not in normal mesothelial MeT-5A cells. Combination treatment up-regulated the levels of p-p53, cleaved caspase-3, and cleaved PARP proteins. Gene silencing with p53-targeting siRNA attenuated the sensitivity of cells to the combined treatment of two compounds. Analyses of p53 DNA binding assay, p53 reporter gene assay, and RTP-CR toward p53-regulated genes, including Bax, PUMA, Noxa and p21, demonstrated that induced p-p53 is transcriptionally active. These results were further confirmed by the siRNA-mediated knockdown of p53 gene. Combination treatment significantly caused the accumulation of cells at G1 phase with the increases in the sub-G0/G1 peak, DNA ladder, nuclear fragmentation, and caspase-3/7 activity. Taken together, these results demonstrate that resveratrol and clofarabine synergistically elicit apoptotic signal via a p53-dependent pathway, and provide a scientific rationale for clinical evaluation of resveratrol as a promising chemopotentiator in MM.
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PMID:Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53. 2423 93

We have created models to predict cleavage sites for several human proteases including caspase-1, caspase-3, caspase-6, caspase-7, cathepsin B, cathepsin D, cathepsin G, cathepsin K, cathepsin L, elastase-2, granzyme A, granzyme B, matrix metallopeptidase-2 (MMP2), MMP7, MMP9, thrombin, and trypsin-1. Rather than representing the sequence pattern around the potential cleavage site through a series of flags with each flag representing one of the 20 standard amino acids, we first represent each amino acid by its calculated properties. For these calculated properties, we use validated cheminformatic descriptors, such as molecular weight, logP, and polar surface area, of the individual amino acids. Finally, the cleavage site-specific descriptors are calculated through various combinations of the individual amino acid descriptors for the residues surrounding the cleavage site. Some of these combinations do not take into account the location of the residue, as long as it is in a prescribed neighborhood of the potential cleavage site, whereas others are sensitive to the precise order of the residues in the sequence. The key advantage of this approach is that it allows one to perform meaningful calculations with nonstandard amino acids for which little or no data exists. Finally, using both docking and molecular dynamics simulations, we examine the potential for and limitations of protease crystal structures to impact the design of proteolytically stable peptides.
Biopolymers 2015 Nov
PMID:A combined cheminformatic and bioinformatic approach to address the proteolytic stability challenge in peptide-based drug discovery. 2627 Mar 98