Peptidyl ?-homo-aspartals (3-amino-4-carboxybutyraldehydes): New specific inhibitors of caspases
Interleukin-1[beta] (IL-1[beta])-converting enzyme (ICE, caspase-1) processes the IL-1[beta] precursor to mature inflammatory cytokine IL-1[beta]. ICE has been identified as a unique cysteine protease, which cleaves Asp-X bonds, shows resistance to E-64 (an inhibitor of most cysteine proteases) and...
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| Published in: | Biopolymers Vol. 51; no. 1; pp. 109 - 118 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
1999
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Interleukin-1[beta] (IL-1[beta])-converting enzyme (ICE, caspase-1) processes the IL-1[beta] precursor to mature inflammatory cytokine IL-1[beta]. ICE has been identified as a unique cysteine protease, which cleaves Asp-X bonds, shows resistance to E-64 (an inhibitor of most cysteine proteases) and has a primary structure that is homologous to CED-3, a protein required for apoptosis (programmed cell death) in the nematode Caenorhabditis elegans, and to mammalian cysteine proteases that initiate and execute apoptosis, e.g., apopain/CPP32/caspase-3. The inhibitors of the ICE/CED-3 family or caspases, as they are called recently, may constitute therapeutic agents for amelioration of inflammatory and apoptosis-associated diseases. The most efficient ICE inhibitors are peptide aldehydes and peptidyl chloro or (acyloxy)methanes. A recent study revealed that both D- and L-Asp are accepted by ICE at the P sub(1) of such inhibitors, and the peptidyl (acyloxy)methane analogues having the [beta]-homo-aspartyl residue [--NH--CH(CH sub(2)COOH)--C H sub(2)CO--] are inactive. These findings we reexamined in terms of two issues. (a) ICE's resistance to E-64. Since it was thought to be caused by the enzyme's unique substrate specificity, we prepared substrate-based analogues, which were not inhibitory suggesting significant structural difference between the active centers of ICE and papain-like enzymes. (b) Tolerance for D-stereochemistry at the P sub(1) of these inhibitors. In view of the mechanism of cysteine protease inhibition by peptidyl X-methanes, we thought that this phenomenon should be a general characteristic of cysteine proteases and the hAsp-containing analogues should behave as reversible inhibitors. Here, we analyzed the inhibition of ICE and apopain in comparison with that of papain, thrombin, and trypsin by peptide L/D-[alpha]-aldehydes and their L-[beta]-homo-aldehyde [--NH--CH(R)--CH sub(2)-- CHO] analogues. The following results were found. (1) The peptidyl L-[beta]-homo-aspartals are potent inhibitors for caspases. (2) The L-[beta]-homo analogues of peptide aldehyde inhibitors designed for other proteases are not inhibitory. (3) Unlike trypsin and thrombin (serine proteases), papain (cysteine protease) shows tolerance for D-stereochemistry at the P sub(1) site of peptide aldehydes in proportion to the lability of the [alpha]-hydrogen of the P sub(1)-D-residue. The complete tolerance of ICE for P sub(1)-D-Asp may arise from this residue's high tendency to epimerization. (4) Reaction of cysteine proteases with peptide aldehyde or peptidyl X-methane inhibitors containing P sub(1)-D-residues may include [alpha]-proton abstraction followed by asymmetric induction leading to P sub(1)-L-residue-containing products. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0006-3525 1097-0282 |
| DOI: | 10.1002/(SICI)1097-0282(1999)51:1<109::AID-BIP12>3.0.CO;2-S |