Reversible inhibition of cathepsin L-like proteases by 4-mer pseudopeptides

FEBS Lett. 2001 Nov 2;507(3):362-6. doi: 10.1016/s0014-5793(01)03008-3.


A library of 121 pseudopeptides was designed to develop reversible inhibitors of trypanosomal enzymes (cruzain from Trypanosoma cruzi and congopain from Trypanosoma congolense). The peptides share the framework: Cha-X1-X2-Pro (Cha=cyclohexyl-alanine, X1 and X2 were phenylalanyl analogs), based on a previous report [Lecaille, F., Authié, E., Moreau, T., Serveau, C., Gauthier, F. and Lalmanach, G. (2001) Eur. J. Biochem. 268, 2733-2741]. Five peptides containing a nitro-substituted aromatic residue (Tyr/Phe) and one a 4-chloro-phenylalanine at the X1 position, and 3-(2-naphthyl)-alanine, homocyclohexylalanine or 3-nitro-tyrosine (3-NO(2)-Tyr) at the X2 position, were selected. They inhibited congopain more effectively than cruzain, except Cha-4-NO(2)-Phe-3-NO(2)-Tyr-Pro which bound the two parasitic enzymes similarly. Among this series, Cha-3-NO(2)-Tyr-HoCha-Pro and Cha-4-NO(2)-Phe-3-NO(2)-Tyr-Pro are the most selective for congopain relative to host cathepsins. No hydrolysis occurred upon prolonged incubation time with purified enzymes. In addition introduction of non-proteogenic residues in the peptidyl backbone greatly enhanced resistance to proteolysis by mammalian sera.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cathepsin B / antagonists & inhibitors
  • Cathepsin L
  • Cathepsins / antagonists & inhibitors*
  • Cathepsins / metabolism
  • Coumarins / metabolism
  • Cysteine Endopeptidases / drug effects
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dipeptides / metabolism
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology*
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Protozoan Proteins / antagonists & inhibitors
  • Structure-Activity Relationship


  • 3-cyclohexylalanyl-3-nitrotyrosyl-homocyclohexylalanyl-proline
  • 3-cyclohexylalanyl-4-nitrophenylalanyl-3-nitrotyrosyl-proline
  • Coumarins
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Oligopeptides
  • Peptides
  • Protozoan Proteins
  • benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide
  • Cathepsins
  • Cysteine Endopeptidases
  • congopain
  • cruzain, Trypanosoma cruzi
  • Cathepsin B
  • Cathepsin L