Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors

Wang, Zhigang; Watt, W.; Brooks, Nathan; Harris, Melissa S.; Urban, Ján; Boatman, Douglas; McMillan, Michael; Kahn, Michael; Heinrikson, Robert L.; Finzel, B.C.; Wittwer, Arthur J.; Blinn, James R.; Kamtekar, S.; Tomasselli, Alfredo G.

doi:10.1016/j.bbapap.2010.05.007

Cited by 41 publications

(48 citation statements)

References 61 publications

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“…One of the urazolering peptomimetic inhibitors which bind at the active site was also found to bind near the dimer interface of caspase-8 [72]. Some of the interacting residues of caspase-8 are Tyr334, Thr337, Glu396, and Phe399.…”

Section: Allosteric Inhibitorsmentioning

confidence: 97%

“…These include urazolopyrazine-based "-strand peptidomimeticsdesigned as inhibitors for caspase-3 and caspase-8, [72] hydantoin-based peptidomimetics as inhibitors of caspase-3 [73], dipeptidylaspartylfluormethylketones with unnatural amino acids [74], 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides, [75] 8,5-fused bicyclic compounds, [76] and peptidomimetics containing a caprolactam ring [77].…”

Section: Active Site Inhibitorsmentioning

confidence: 99%

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Caspases – Key Players in Apoptosis

Cade

Clark

2015

Proteases in Apoptosis: Pathways, Protocols and Translational Advances

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Caspases are the terminal proteases involved in apoptosis, as well as being involved in inflammation. The apoptotic caspases can be classified as either initiator or effector caspases based on both their position in the caspase cascade and their activation mechanism. Initiator caspases require dimerization to be activated, and cleavage of a loop called the intersubunit linker stabilizes the active enzyme. Effector caspases, on the other hand, are found as dimers in the cell and cleavage of the intersubunit linker is the key step in their activation.The name caspase is short for cysteinyl aspartate-specific protease. As their name suggests, these enzymes hydrolyze peptide bonds after certain aspartate residues using a catalytic cysteine (with the aid of an active-site histidine residue). Caspases can be inhibited by endogenous inhibitors such as XIAP, by synthetic inhibitors which target either the active site or an allosteric site, or by post-translational modification. Further research is needed to find novel activators and inhibitors of caspases to treat diseases which involve misregulation of apoptosis.

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Section: Allosteric Inhibitorsmentioning

confidence: 97%

Section: Active Site Inhibitorsmentioning

confidence: 99%

Caspases – Key Players in Apoptosis

Cade

Clark

2015

Proteases in Apoptosis: Pathways, Protocols and Translational Advances

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“…S 1 to S 4 [1,20]. Effective circumventive measures are being taken by pharmaceutical companies to substitute peptide inhibitor characteristics such as poor membrane penetration, short in vivo half-life and labile pharmacokinetic properties by chemically reactive small molecules to pursue potent inhibition of caspase-3 activity [1,[17][18][19]. Caspase-3 inhibitors constitute three essential parts: an element for active site recognition, Asp at P 1 position and an electrophilic warhead (e.g.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Multi-level structure-based pharmacophore modelling of caspase-3-non-peptide complexes: Extracting essential pharmacophore features and its application to virtual screening

Kumar

Jha

2016

Chemico-Biological Interactions

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“…These results indicate that discrimination against caspase-3 is attributable to the CV8/9-AOMK recognition and reversible binding event with active site residues that results in the E-I reversible complex rather than covalent attachment to the catalytic cysteine and EI formation (Figure 3). 28 Notably, k inact /K i values were >1000-fold higher for CV8/9-AOMK against caspases-8 and -9 with only a 3-fold difference among caspases-3, -8, and -9 for Ac-LETD-AOMK (Figure 3). The significant CV8/9-AOMK selectivity for caspases-8 and -9 is also accompanied by a marked decrease in potency and coincides with our observations for the IC 50 studies (Figures 2 and 3).…”

mentioning

confidence: 92%

Selective Inhibition of Initiator versus Executioner Caspases Using Small Peptides Containing Unnatural Amino Acids

et al. 2014

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Caspases are fundamental to many essential biological processes, including apoptosis, differentiation, and inflammation. Unregulated caspase activity is also implicated in the development and progression of several diseases, such as cancer, neurodegenerative disorders, and sepsis. Unfortunately, it is difficult to determine exactly which caspase(s) of the 11 isoforms that humans express is responsible for specific biological functions. This lack of resolution is primarily due to highly homologous active sites and overlapping substrates. Currently available peptide-based inhibitors and probes are based on specificity garnered from peptide substrate libraries. For example, the canonical tetrapeptide LETD was discovered as the canonical sequence that is optimally recognized by caspase-8; however, LETD-based inhibitors and substrates promiscuously bind to other isoforms with equal affinity, including caspases-3, -6, and -9. In order to mitigate this problem, we report the identification of a new series of compounds that are >100-fold selective for inhibiting the initiator caspases-8 and -9 over the executioner caspases-3, -6, and -7.C aspases are a family of cysteine-dependent aspartatedirected proteases with 11 human isoforms that are traditionally known for their indispensible roles in the initiation (caspases-2, -8, -9, -10) and execution (caspases-3, -6, -7) of apoptosis. 1 Other family members, including caspases-1, -4, and -5, are important regulators of inflammation and induce pyroptotic cell death as a result of microbial infection. 2 Intriguingly, recent reports implicate caspase activity as being critical for a variety of other essential biological processes, such as DNA repair signaling and tumor suppression, 3 skeletal muscle differentiation, 4 B-cell proliferation, 5 dendritic pruning and neuronal plasticity, 6 embryonic stem cell differentiation through Nanog cleavage, 7 nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) activation, 8 lymphocyte and monocyte differentiation and development, 9 and keratinocyte differentiation and skin barrier formation. 10 The utility of caspase-dependent proteolysis in an array of cellular functions is continually expanding, and additional caspase roles will likely be discovered with the development of highly potent and specific chemical inhibitors and probes.Active caspases have many significant irreversible consequences and as such are stored as inactive proenzymes, or procaspases, inside of the cell. 11 Intriguingly, several small molecules have been identified in high-throughput screens that promote executioner procaspase maturation using in vitro and in vivo models. 12−14 Aberrant caspase activity is implicated in the development and progression of several diseases, such as neurodegenerative disorders, 15 cancer, 16 cardiovascular disease, 17 and sepsis. 18 Moreover, caspases represent potential drug discovery targets for the treatment of these diseases, and it is therefore imperative to elucidate the exact biological roles of each i...

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Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors

Cited by 41 publications

References 61 publications

Caspases – Key Players in Apoptosis

Caspases – Key Players in Apoptosis

Multi-level structure-based pharmacophore modelling of caspase-3-non-peptide complexes: Extracting essential pharmacophore features and its application to virtual screening

Selective Inhibition of Initiator versus Executioner Caspases Using Small Peptides Containing Unnatural Amino Acids

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