کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1931398 | 1050551 | 2010 | 6 صفحه PDF | دانلود رایگان |
A series of substrate-based α-keto-β-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 (Ki = 0.3 nM) but also blocking its processing of pro-interleukin-1beta (pro-IL-1β). 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 (Ki = 0.26 nM) yet only functions as a comparatively modest inhibitor of caspase-1 (Ki = 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 in-vitro.
Research highlights
► Substrate-derived peptide glyoxals are potent caspase inhibitors.
► Ki values similar to and in some cases lower than peptide aldehydes can be obtained.
► Good discrimination is possible in some but not all cases.
► Ac-Asp-Glu-Val-Asp-glyoxal does not inhibit the development of apoptosis in-vitro.
► pal-Tyr-Val-Ala-Asp-glyoxal blocks caspase-1 cleavage of recombinant pro-IL-1β.
Journal: Biochemical and Biophysical Research Communications - Volume 402, Issue 3, 19 November 2010, Pages 483–488