ChemInform Abstract: Conformationally Constrained Inhibitors of Caspase-1 (Interleukin-1β Converting Enzyme) and of the Human CED-3 Homologue Caspase-3 (CPP32, Apopain)

ChemInform ◽  
2010 ◽  
Vol 30 (6) ◽  
pp. no-no
Author(s):  
D. S. KARANEWSKY ◽  
X. BAI ◽  
S. D. LINTON ◽  
J. F. KREBS ◽  
J. WU ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Interleukin 1Β ◽  
Converting Enzyme ◽  
Conformationally Constrained ◽  
Caspase 1

scholarly journals Caspase-1 (interleukin-1β-converting enzyme) is inhibited by the human serpin analogue proteinase inhibitor 9

1999 ◽  
Vol 342 (3) ◽  
pp. 655-665 ◽  
Author(s):  
Robert R. ANNAND ◽  
Jeffrey R. DAHLEN ◽  
Cindy A. SPRECHER ◽  
Piet DE DREU ◽  
Donald C. FOSTER ◽  
...  
Keyword(s):  
Proteinase Inhibitor ◽  
Caspase 3 ◽  
Interleukin 1Β ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Cysteine Proteinases ◽  
Converting Enzyme ◽  
Caspase 1 ◽  
Proteinase Inhibitor 9 ◽  
Hydrolysis Of

The regulation of caspases, cysteine proteinases that cleave their substrates after aspartic residues, is poorly understood, even though they are involved in tightly regulated cellular processes. The recently discovered serpin analogue proteinase inhibitor 9 (PI9) is unique among human serpin analogues in that it has an acidic residue in the putative specificity-determining position of the reactive-site loop. We measured the ability of PI9 to inhibit the amidolytic activity of several caspases. The hydrolysis of peptide substrates by caspase-1 (interleukin-1β-converting enzyme), caspase-4 and caspase-8 is inhibited by PI9 in a time-dependent manner. The rate of reaction of caspase-1 with PI9, as well as the rate of substrate hydrolysis of the initial caspase-PI9 complex, shows a hyperbolic dependence on the concentration of PI9, indicative of a two-step kinetic mechanism for inhibition with an apparent second-order rate constant of 7×102 M-1˙s-1. The hydrolysis of a tetrapeptide substrate by caspase-3 is not inhibited by PI9. The complexes of caspase-1 and caspase-4 with PI9 can be immunoprecipitated but no complex with caspase-3 can be detected. No complex can be immunoprecipitated if the active site of the caspase is blocked with a covalent inhibitor. These results show that PI9 is an inhibitor of caspase-1 and to a smaller extent caspase-4 and caspase-8, but not of the more distantly related caspase-3. PI9 is the first example of a human serpin analogue that inhibits members of this class of cysteine proteinases.

In vivo study of motoneuron death induced by nerve injury in mice deficient in the caspase 1/ interleukin-1β-converting enzyme

Neuroscience ◽  
2000 ◽  
Vol 98 (3) ◽  
pp. 573-583 ◽  
Author(s):  
F. de Bilbao ◽  
P. Giannakopoulos ◽  
A. Srinivasan ◽  
M. Dubois-Dauphin
Keyword(s):  
Nerve Injury ◽  
Interleukin 1Β ◽  
In Vivo Study ◽  
Converting Enzyme ◽  
Caspase 1

Novel irreversible caspase-1 inhibitor attenuates the maturation of intracellular interleukin-1β

2007 ◽  
Vol 85 (1) ◽  
pp. 56-65 ◽  
Author(s):  
Xue-Qin Ma ◽  
Hua-Jie Zhang ◽  
Ya-Hui Zhang ◽  
Yi-Hua Chen ◽  
Fang Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokines ◽  
Caspase 3 ◽  
Inflammatory Diseases ◽  
Interleukin 1Β ◽  
Interleukin 18 ◽  
Caspase 1

. Caspase-1, the most efficient enzyme in processing the proinflammatory cytokines interleukin 1β and interleukin 18 in humans, is associated with inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and some neuronal diseases. We previously reported that isoquinoline-1,3,4-trione and its derivatives are novel caspase-3 inhibitors that could attenuate apoptosis in vitro and in vivo. Here we report a novel derivative of isoquinoline-1,3,4-trione that is highly potent in inhibiting caspase-1 activity in an irreversible and slow-binding manner, thus inhibiting cellular caspase-1 activity and the maturation of interleukin 1β in U-937 cells.

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