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

FEBS Letters

Lalmanach, Gilles¹  Lecaille, Fabien¹  Cotton, Joël³  Boll-Bataillé, Emmanuelle¹  McKerrow, James H²  Gauthier, Francis¹  Ferrer-Di Martino, Michèle¹ 

[1] Laboratoire d'Enzymologie et Chimie des Protéines, INSERM EMI-U 00-10, Université François Rabelais, Faculté de Médecine, 2 bis Boulevard Tonnellé, F-37032 Tours Cedex, France;Department of Pathology, University of California, San Francisco, CA, USA;CEA, Département d'Ingénierie et d'Etudes des Protéines, Gif s/Yvette, France

关键词: Cysteine protease;    Cathepsin;    Phe analog;    Pseudopeptide;    Trypanosome;    AMC;    7-amino-4-methyl-coumarin hydrochloride;    CP;    cysteine protease;    DIPEA;    N;    N′-diisopropylethylamine;    HBTU;    2-(1H-benzotriazol-1-yl)-1;    1;    3;    3-tetramethyluronium hexafluorophosphate;    NMP;    N-methyl-2-pyrrolidinone;    Cha;    3-cyclohexyl-alanine;    Chg;    cyclohexyl-glycine;    Phg;    phenyl-glycine;    HoCha;    homocyclohexyl-alanine;    Hof;    homophenyl-alanine;    4-Cl-Phe;    4-chloro-phenylalanine;    3;    4-Cl2-Phe;    3;    4-dichloro-phenylalanine;    Nal2;    3-(2-naphthyl)-alanine;    4-NO2-Phe;    4-nitro-phenylalanine;    3-NO2-Tyr;    3-nitro-tyrosine;   

DOI  :  10.1016/S0014-5793(01)03008-3

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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-NO₂-Tyr) at the X2 position, were selected. They inhibited congopain more effectively than cruzain, except Cha-4-NO₂-Phe-3-NO₂-Tyr-Pro which bound the two parasitic enzymes similarly. Among this series, Cha-3-NO₂-Tyr-HoCha-Pro and Cha-4-NO₂-Phe-3-NO₂-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.

【 授权许可】

Unknown