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[摘要]：A series of substrate-based alpha-keto-beta-aldehyde (glyoxal) sequences have been synthesised and evaluated as inhibitors of the caspase family of cysteine proteases A number of potent inhibitor sequences have been identified For example, a palmitic acid containing sequence pal-Tyr-Val-Ala-Asp-glyoxal was demonstrated to be an extremely effective inhibitor of caspase-1, inhibiting not only the action of the protease against synthetic fluorogenic substrates (K-i = 0 3 nM) but also blocking its processing of pro-interleukin-1beta (pro-IL-1 beta) In addition, the peptide Ac-Asp-Glu-Val-Asp-glyoxal, which is based on the consensus cleavage sequence for caspase-3, is a potent inhibitor of this protease (K-i = 0 26 nM) yet only functions as a comparatively modest inhibitor of caspase-1 (K-i = 451 nM) Potent inhibitor sequences were also identified for caspases-6 and -8. However, the degree of discrimination between the family members is limited The ability of Ac-Asp-Glu-Val-Asp-glyoxal to block caspase-3 like activity in whole cells and to delay the development of apoptosis was assessed When tested against caspase-3 like activity in cell lysates. Ac-Asp-Glu-Val-Asp-glyoxal displayed effective inhibition similar to that observed against recombinant caspase-3 Treatment of whole cells with this potent caspase-3 inhibitor was however, not sufficient to significantly stall the development of apoptosis (C) 2010 Elsevier Inc All rights reserved |
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