title: Reversible inhibition of cathepsin L-like proteases by 4-mer pseudopeptides.
abstract: 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.
authors.affiliation: Laboratoire d"Enzymologie et Chimie des Protéines, INSERM EMI-U 0010, Université Francois Rabelais, Faculté de Médecine, Tours, France.
authors.forename: F
authors.initials: F
authors.lastname: Lecaille
authors.forename: J
authors.initials: J
authors.lastname: Cotton
authors.forename: J H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: M
authors.initials: M
authors.lastname: Ferrer-Di Martino
authors.forename: E
authors.initials: E
authors.lastname: Boll-Bataillé
authors.forename: F
authors.initials: F
authors.lastname: Gauthier
authors.forename: G
authors.initials: G
authors.lastname: Lalmanach
mesh_terms: D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004151:Dipeptides / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C442324:3-cyclohexylalanyl-3-nitrotyrosyl-homocyclohexylalanyl-proline; C442325:3-cyclohexylalanyl-4-nitrophenylalanyl-3-nitrotyrosyl-proline; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D009842:Oligopeptides; D010455:Peptides; D015800:Protozoan Proteins; C021159:benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C084086:congopain; C074032:cruzain, Trypanosoma cruzi; D002401:Cathepsin B; D056668:Cathepsin L