1. Preparation and evaluation of peptidic aspartyl hemiacetals as reversible inhibitors of interleukin-l β converting enzyme (ICE)
- Author
-
Todd L. Graybill, Roland E. Dolle, Mark A. Ator, Robert E. Miller, and Carla T. Helaszek
- Subjects
chemistry.chemical_classification ,Dipeptide ,biology ,Stereochemistry ,Context (language use) ,Tripeptide ,Biochemistry ,Aldehyde ,chemistry.chemical_compound ,chemistry ,Enzyme inhibitor ,Peptide synthesis ,biology.protein ,Hemiacetal ,Semicarbazone - Abstract
Aspartyl aldehyde, Ac-Tyr-Val-Ala-Asp-H 1 (L-709,049), has been reported to be a potent, reversible inhibitor of interleukin-1 beta converting enzyme (ICE) [Thornberry, N.A. et al. (1992) Nature (London) 356, 768-774]. In the context of our own work, we have developed a general synthetic approach to peptidic aspartyl aldehydes. Semicarbazone derivative, H-Asp(Ot-Bu)-Sc 4, was identified as a stable, masked aspartyl aldehyde equivalent. We have used 4 to synthesize a series of mono-, di- and tripeptide aldehydes, and multigram quantities of Ac-Tyr-Val-Ala-Asp-H 1, Ac-Tyr-Val-Lys-Asp-Sc 21 and Ac-Tyr-Val-Lys-Asp-H 2. Biological evaluation of these aspartyl aldehydes and derivatives suggests that the tripeptide scaffold, Z-Val-Ala-Asp, is a peptide scaffold that retains good potency and selectivity for ICE.
- Published
- 2009