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The Inhibitor Profiling of the Caspase Family of Proteases Using Substrate-Derived Peptide Glyoxals

The Inhibitor Profiling of the Caspase Family of Proteases Using Substrate-Derived Peptide Glyoxals

Diarmaid J Murphy, Brian Walker, Ciara A Ryan, S Lorraine Martin

Biochem Biophys Res Commun. 2010 Nov 19;402(3):483-8.

PMID: 20955686

Abstract:

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 (K(i)=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 (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 in-vitro.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4241003	Caspase 8 Substrate, fluorogenic			Price

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