1T32

A Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase with Therapeutic Efficacy in Animals Models of Inflammation

1T32 の概要

• エントリーDOI: 10.2210/pdb1t32/pdb
• 関連するPDBエントリー: 1CGH
• 分子名称: Cathepsin G, SULFATE ION, 2-[3-({METHYL[1-(2-NAPHTHOYL)PIPERIDIN-4-YL]AMINO}CARBONYL)-2-NAPHTHYL]-1-(1-NAPHTHYL)-2-OXOETHYLPHOSPHONIC ACID, ... (4 entities in total)
• 機能のキーワード: inflammation inhibitor serine protease, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell surface: P08311
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26635.21

構造登録者

de Garavilla, L.,Greco, M.N.,Giardino, E.C.,Wells, G.I.,Haertlein, B.J.,Kauffman, J.A.,Corcoran, T.W.,Derian, C.K.,Eckardt, A.J.,Abraham, W.M.,Sukumar, N.,Chen, Z.,Pineda, A.O.,Mathews, F.S.,Di Cera, E.,Andrade-Gordon, P.,Damiano, B.P.,Maryanoff, B.E. (登録日: 2004-04-23, 公開日: 2005-03-01, 最終更新日: 2023-08-23)

主引用文献

de Garavilla, L.,Greco, M.N.,Sukumar, N.,Chen, Z.W.,Pineda, A.O.,Mathews, F.S.,Di Cera, E.,Giardino, E.C.,Wells, G.I.,Haertlein, B.J.,Kauffman, J.A.,Corcoran, T.W.,Derian, C.K.,Eckardt, A.J.,Damiano, B.P.,Andrade-Gordon, P.,Maryanoff, B.E.
A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo.
J.Biol.Chem., 280:18001-18007, 2005

PubMed Abstract: Certain leukocytes release serine proteases that sustain inflammatory processes and cause disease conditions, such as asthma and chronic obstructive pulmonary disease. We identified beta-ketophosphonate 1 (JNJ-10311795; RWJ-355871) as a novel, potent dual inhibitor of neutrophil cathepsin G (K(i) = 38 nm) and mast cell chymase (K(i) = 2.3 nm). The x-ray crystal structures of 1 complexed with human cathepsin G (1.85 A) and human chymase (1.90 A) reveal the molecular basis of the dual inhibition. Ligand 1 occupies the S(1) and S(2) subsites of cathepsin G and chymase similarly, with the 2-naphthyl in S(1), the 1-naphthyl in S(2), and the phosphonate group in a complex network of hydrogen bonds. Surprisingly, however, the carboxamido-N-(naphthalene-2-carboxyl)piperidine group is found to bind in two distinct conformations. In cathepsin G, this group occupies the hydrophobic S(3)/S(4) subsites, whereas in chymase, it does not; rather, it folds onto the 1-naphthyl group of the inhibitor itself. Compound 1 exhibited noteworthy anti-inflammatory activity in rats for glycogen-induced peritonitis and lipopolysaccharide-induced airway inflammation. In addition to a marked reduction in neutrophil influx, 1 reversed increases in inflammatory mediators interleukin-1alpha, interleukin-1beta, tissue necrosis factor-alpha, and monocyte chemotactic protein-1 in the glycogen model and reversed increases in airway nitric oxide levels in the lipopolysaccharide model. These findings demonstrate that it is possible to inhibit both cathepsin G and chymase with a single molecule and suggest an exciting opportunity in the treatment of asthma and chronic obstructive pulmonary disease.

PubMed: 15741158
DOI: 10.1074/jbc.M501302200

実験手法

X-RAY DIFFRACTION (1.85 Å)