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Characterization of a Novel and Specific Inhibitor for the Pro-apoptotic Protease Omi/HtrA2

2003; Elsevier BV; Volume: 278; Issue: 13 Linguagem: Inglês

10.1074/jbc.m212819200

1083-351X

Lucia Cilenti, Younghee Lee, Sibylle Hess, Srinivasa M. Srinivasula, Kwon Moo Park, Daniela Junqueira, Hedvika Davis, Joseph V. Bonventre, Emad S. Alnemri, Antonis S. Zervos,

Calpain Protease Function and Regulation

Omi/HtrA2 is a mammalian serine protease with high homology to bacterial HtrA chaperones. Omi/HtrA2 is localized in mitochondria and is released to the cytoplasm in response to apoptotic stimuli. Omi/HtrA2 induces cell death in a caspase-dependent manner by interacting with the inhibitor of apoptosis protein as well as in a caspase-independent manner that relies on its protease activity. We describe the identification and characterization of a novel compound as a specific inhibitor of the proteolytic activity of Omi/HtrA2. This compound (ucf-101) was isolated in a high throughput screening of a combinatorial library using bacterially made Omi-(134–458) protease and fluorescein-casein as a generic substrate. ucf-101 showed specific activity against Omi/HtrA2 and very little activity against various other serine proteases. This compound has a natural fluorescence that was used to monitor its ability to enter mammalian cells. ucf-101, when tested in caspase-9 (−/−) null fibroblasts, was found to inhibit Omi/HtrA2-induced cell death.