Preparation and evaluation of peptidic aspartyl hemiacetals as reversible inhibitors of interleukin‐l β converting enzyme (ICE)

TODD L. GRAYBILL, ROLAND E. DOLLE, CARLA T. HELASZEK, ROBERT E. MILLER, MARK A. ATOR

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Aspartyl aldehyde, Ac‐Tyr‐Val‐Ala‐Asp‐H 1 (L–709,049), has been reported to be a potent, reversible inhibitor of interleukin‐1β 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.

Original languageEnglish
Pages (from-to)173-182
Number of pages10
JournalInternational Journal of Peptide and Protein Research
Volume44
Issue number2
DOIs
StatePublished - Aug 1994
Externally publishedYes

Keywords

  • ICE
  • aspartyl aldehyde
  • converting enzyme
  • cysteine protease
  • hemiacetal
  • inhibitor
  • interleukin‐1β
  • preparation
  • semicarbazone

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