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Reversible inhibition of cathepsin L‐like proteases by 4‐mer pseudopeptides
Author(s) -
Lecaille Fabien,
Cotton Joël,
McKerrow James H,
Ferrer-Di Martino Michèle,
Boll-Bataillé Emmanuelle,
Gauthier Francis,
Lalmanach Gilles
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)03008-3
Subject(s) - chemistry , cathepsin , peptide , residue (chemistry) , proteolysis , enzyme , trypanosoma cruzi , biochemistry , phenylalanine , cathepsin l , hydrolysis , tyrosine , oligopeptide , alanine , stereochemistry , proteases , cathepsin b , amino acid , parasite hosting , world wide web , computer science
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.