Aza-peptide epoxides: potent and selective inhibitors of Schistosoma mansoni and pig kidney legumains (asparaginyl endopeptidases)

Biol Chem. 2003 Dec;384(12):1613-8. doi: 10.1515/BC.2003.179.


Aza-peptide epoxides are a new class of irreversible cysteine protease inhibitors. Derivatives containing a P1 aza-asparagine residue are specific for Schistosoma mansoni and pig kidney legumains, which are clan CD cysteine proteases. The inhibitors have second-order rate constants of up to 10(4) M(-1) s(-1) with pig kidney legumain and IC50 values as low as 45 nM with S. mansoni legumain. The most potent epoxides contain an ester moiety with S,S stereochemistry attached to the epoxide. Interestingly, amide and amino acid derivatives of the epoxysuccinate moiety were not inhibitors of legumain, while disubstituted amide derivatives are quite potent. The inhibitors have little or no inhibitory activity with other proteases such as caspases, chymotrypsin, papain, cathepsin B, granzyme B, and various aspartyl proteases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aza Compounds / chemistry
  • Coumarins / metabolism
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / metabolism*
  • Epoxy Compounds / chemistry
  • Kidney / chemistry
  • Kidney / enzymology*
  • Kinetics
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Recombinant Proteins / metabolism
  • Schistosoma mansoni / enzymology*
  • Spectrometry, Fluorescence
  • Stereoisomerism
  • Swine


  • Aza Compounds
  • Coumarins
  • Cysteine Proteinase Inhibitors
  • Epoxy Compounds
  • Oligopeptides
  • Recombinant Proteins
  • benzyloxycarbonylalanyl-alanyl-asparaginyl-4-methyl-7-coumarylamide
  • Cysteine Endopeptidases
  • asparaginylendopeptidase