Caspases as Targets for Anti-Inflammatory and Anti-Apoptotic Drug Discovery

Talanian, Robert V.; Brady, Kenneth D.; Cryns, Vincent L.

doi:10.1021/jm000060f

Cited by 106 publications

(83 citation statements)

References 281 publications

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“…Since these synthetic peptide inhibitors are relatively poor in their ability to discriminate among different caspase family members, these reagents are best suited to demonstrate the involvement of caspases and apoptosis in general in a particular process, rather than pinpointing a role for a specific caspase. For further detailed reviews, see Livingston, (1997), Ekert et al (1999a), Rudel (1999), Talanian et al (2000).…”

Section: Peptide-based Caspase Inhibitorsmentioning

confidence: 99%

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A decade of caspases

2003

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Section: Peptide-based Caspase Inhibitorsmentioning

confidence: 99%

“…Since the improper regulation of apoptosis contributes to a variety of diseases, caspases represent promising therapeutic targets (Nicholson, 2000;Talanian et al, 2000). In addition to their role in apoptosis, caspases may also be involved in the direct cleavage of diseaseassociated factors.…”

Section: Disease-related Proteinsmentioning

confidence: 99%

A decade of caspases

2003

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“…The class of human inf lammator y caspases-1, -4, and -5 is involved in driving innate immune responses after pathogen stimulation and has been of considerable interest for basic and medicinal purposes (7,8). Although caspase-1 shares only a 20-30% amino acid sequence identity with the apoptotic caspases, it too contains a cavity at the dimer interface.…”

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confidence: 99%

A common allosteric site and mechanism in caspases

Scheer

Romanowski

Wells

2006

Proc. Natl. Acad. Sci. U.S.A.

153

161

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We present a common allosteric mechanism for control of inflammatory and apoptotic caspases. Highly specific thiol-containing inhibitors of the human inflammatory caspase-1 were identified by using disulfide trapping, a method for site-directed small-molecule discovery. These compounds became trapped by forming a disulfide bond with a cysteine residue in the cavity at the dimer interface Ϸ15 Å away from the active site. Mutational and structural analysis uncovered a linear circuit of functional residues that runs from one active site through the allosteric cavity and into the second active site. Kinetic analysis revealed robust positive cooperativity not seen in other endopeptidases. Recently, disulfide trapping identified a similar small-molecule site and allosteric transition in the apoptotic caspase-7 that shares only a 23% sequence identity with caspase-1. Together, these studies show a general small-molecule-binding site for functionally reversing the zymogen activation of caspases and suggest a common regulatory site for the allosteric control of inflammation and apoptosis.procaspase ͉ allosteric regulation ͉ apoptosis ͉ fragment-based discovery ͉ inflammation C aspases are dimeric thiol endopeptidases that cleave specific proteins after aspartic acid residues and drive apoptosis or inflammation (for review, see refs. 1 and 2). Although of considerable medical interest, the active sites of caspases have been very difficult to target with drug-like compounds owing to the enzyme's preference for negatively charged chemotypes with electrophilic warheads that engage the catalytic cysteine (3).In past work to develop alternative small-molecule inhibitors to the active site of the apoptotic caspase-7, we used a fragmentbased discovery approach called disulfide trapping. This is a site-directed small-molecule-capture approach in which natural or engineered cysteines on the surface of the protein are screened with a library of disulfide-containing small molecules in a redox buffer (4). This approach has been broadly applied in fragment-based drug discovery for both enzymes and challenging protein-protein interface targets (for review see ref. 5). Although the active-site cysteine of caspase-7 failed to yield strong hits from a library of Ϸ10,000 disulfide-containing compounds, several strong inhibitors were found for another cysteine in a cavity at the dimer interface.Procaspase-7, the inactive precursor or zymogen, is known to undergo a large structural transition after auto-or transproteolysis. This transition results in cleavage of the N-terminal 23 residues and an internal cut that yields two large and two small subunits of mature caspase-7. Structural studies of caspase-7 containing the disulfide-trapped inhibitors at the dimerinterface cavity showed that the compounds reversed this structural transition and induced a conformation virtually identical to the zymogen form (6).We wondered whether other caspases could be inhibited by a similar mechanism. The class of human inf lammator y caspases-1, -4, and -5 is...

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“…The amyloid ␤-peptide is derived from proteolysis of the amyloid precursor protein, a reaction catalyzed by ␤-and ␥-secretases (3,4). The enzyme ␤-secretase (BSEC) is essential for nerve cells to form the senile plaques (5)(6)(7)(8)(9). Most current therapeutic approaches to Alzheimer's disease involve finding drugs that block the BSEC catalytic site and disrupt its function.…”

mentioning

confidence: 99%

“…Because of a central role in inflammation and apoptosis, caspases (CASPs) have received enormous research attention (8). Results from nonspecific CASP inhibitors suggest that inhibition of CASPs could be sufficient to block apoptosis (9).…”

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confidence: 99%