Preparation and evaluation of peptidic aspartyl hemiacetals as reversible inhibitors of interleukin-1 beta converting enzyme (ICE).
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.
Graybill
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Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania.
Dolle
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Helaszek
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Miller
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Ator
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D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology*; D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000031:analogs & derivatives*; D020170:Caspase 1; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D001224:Aspartic Acid; D003546:Cysteine Endopeptidases; D020170:Caspase 1