Functionalized N‐aryl azetidinones as novel mechanism‐based inhibitors of neutrophil elastase

FEBS Letters

Boggetto, Nicole¹  Montagne, Jean-Jacques¹  Wakselman, Michel²  Maillard, Jean¹  Vergely, Isabelle¹  Joyeau, Roger²  Okochi, Veronica¹  Kobaiter, Randa²  Reboud-Ravaux, Michèle¹ 

[1] Laboratoire de Bioactivation des Peptides, Institut Jacques Monod, Université de Paris VII, 2 place Jussieu, 75251 Paris Cedex 05, France;Centre National de la Recherche Scientifique, Centre d'Etudes et de Recherches de Chimie Organique Appliquèe, Laboratoire de Chimie Organique Biologique, 2 rue Henry Dunant, 94320 Thials, France

关键词: β-Lactam;    Leukocyte elastase;    Suicide substrate;    HLE;    human leukocyte elastase (EC 3.4.21.37);    PPE;    porcine pancreatic elastase (EC 3.4.21.36);    Suc-Ala3-NA;    succinylalanyl-alanyl-alanine p-nitroanilide;    MeO-Suc-Ala2-Pro-Val-NA;    methoxysuccinyl-alanyl-alanyl-prolyl-valyl p-nitroanilide;    Ac-Tyr-NA;    N-acetyl-L-tyrosine p-nitroanilide;    Bz-Arg-NA;    benzoyl-arginyl p-nitroanilide;    S-2251;    D-valyl-L-leucyl-L-lysine p-nitroanilide;    S-2238;    D-phenylalanine-L-pipecolyl-L-arginine p-nitroanilide;    PNA;    p-nitrophenyl acetate;    NPGB;    p-nitrophenyl p-guanidinobenzoate;    Z-Ala-Ala-Pro-Aala-Ala-ONp;    N-benzyloxycarbonyl-alanyl-alanyl-prolyl-azaalanyl-p-nitrophenyl ester;    DMSO;    dimethylsulfoxide;   

DOI  :  10.1016/0014-5793(91)80517-7

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

A functionalized N-aryl azetidinone has been shown to inactive human leukocyte elastase (HLE) and porcine pancreatic elastase (PPE) by an enzyme-mediated process. The inactivation is characterized by the following kinetic constants at pH 8.0 and 37°C: k _max=0.035 s⁻¹, K ₁=1.2 × 10 ⁻⁴ M for HLE, 0.08 s⁻¹ and 2.7 × 10⁻⁴ M for PPE, respectively. Two parent molecules devoid of the latent leaving group failed to inactive HLE and PPE and behaved as substrates of these enzymes. A suicide mechanism involving the formation of an acyl-enzyme and the simultaneous unmasking of a latent quinonimmonium methide ion which irreversibly reacts with an active site nucleophile. Moreover, the inhibitor is still effective at inhibiting elastase preabsorbed onto elastin.

【 授权许可】

Unknown