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Interleukin-1β-converting enzyme and related proteases as potential targets in inflammation and apoptosis

  • Perspectives Part I. Eucaryotic Host Proteases
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Perspectives in Drug Discovery and Design

Summary

Interleukin-1β-converting enzyme (ICE, EC 3.4.22.36) is the cysteine protease responsible for the production of interleukin-1β in monocytes. Since its discovery in 1989, this enzyme has been the subject of enthusiastic investigation because of the suspected role of this cytokine in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. These studies have culminated in the purification and cloning of the enzyme, development of potent inhibitors, determination of its structure by X-ray crystallography and the development of knockout mice, which have confirmed an important role for this protease in inflammation. Late in 1993, the protease became the subject of further interest because of its homology to CED-3, the product of a gene required for programmed cell death in the nematodeC. elegans. It is now clear that ICE is the first identified member of a new cysteine protease family that includes CED-3 and at least four other human homologues. Although the extent to which ICE itself plays a role in mammalian apoptosis remains controversial, it is clear that at least one of these homologues, CPP32, is an important player. The recognition that members of this family play key biological roles in both inflammation and apoptosis, two extremely attractive targets for therapeutic intervention, has led to intense interest in these proteases.

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Authors and Affiliations

  1. Department of Enzymology, Merck Research Laboratories, R80W-243, USA

    Nancy A. Thornberry

  2. Department of Biochemical and Molecular Pathology, Merck Research Laboratories, R80N-A32, P.O. Box 2000, 07065, Rahway, NJ, U.S.A.

    Douglas K. Miller

  3. Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, H9R 4P8, Pointe Claire-Dorval, PQ, Canada

    Donald W. Nicholson

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  1. Nancy A. Thornberry
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Thornberry, N.A., Miller, D.K. & Nicholson, D.W. Interleukin-1β-converting enzyme and related proteases as potential targets in inflammation and apoptosis. Perspectives in Drug Discovery and Design 2, 389–399 (1995). https://doi.org/10.1007/BF02172032

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