1t32: Difference between revisions

Revision as of 16:09, 21 February 2008

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

OverviewOverview

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.

About this StructureAbout this Structure

1T32 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Cathepsin G, with EC number 3.4.21.20 Full crystallographic information is available from OCA.

ReferenceReference

A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo., de Garavilla L, Greco MN, Sukumar N, Chen ZW, Pineda AO, Mathews FS, Di Cera E, Giardino EC, Wells GI, Haertlein BJ, Kauffman JA, Corcoran TW, Derian CK, Eckardt AJ, Damiano BP, Andrade-Gordon P, Maryanoff BE, J Biol Chem. 2005 May 6;280(18):18001-7. Epub 2005 Feb 28. PMID:15741158

Page seeded by OCA on Thu Feb 21 15:09:18 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1t32.gif|left|200px]]<br />
+[[Image:1t32.gif|left|200px]]<br /><applet load="1t32" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1t32" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1t32, resolution 1.85&Aring;" />
 '''A Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase with Therapeutic Efficacy in Animals Models of Inflammation'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-T32 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and OHH as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cathepsin_G Cathepsin G], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.20 3.4.21.20] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1T32 OCA].
+T32 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=OHH:'>OHH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cathepsin_G Cathepsin G], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.20 3.4.21.20] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T32 OCA].
 ==Reference==
@@ Line 15: / Line 14: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Abraham, W.M.]]
+[[Category: Abraham, W M.]]
 [[Category: Andrade-Gordon, P.]]
-[[Category: Cera, E.Di.]]
+[[Category: Cera, E Di.]]
 [[Category: Chen, Z.]]
-[[Category: Corcoran, T.W.]]
+[[Category: Corcoran, T W.]]
-[[Category: Damiano, B.P.]]
+[[Category: Damiano, B P.]]
-[[Category: Derian, C.K.]]
+[[Category: Derian, C K.]]
-[[Category: Eckardt, A.J.]]
+[[Category: Eckardt, A J.]]
-[[Category: Garavilla, L.de.]]
+[[Category: Garavilla, L de.]]
-[[Category: Giardino, E.C.]]
+[[Category: Giardino, E C.]]
-[[Category: Greco, M.N.]]
+[[Category: Greco, M N.]]
-[[Category: Haertlein, B.J.]]
+[[Category: Haertlein, B J.]]
-[[Category: Kauffman, J.A.]]
+[[Category: Kauffman, J A.]]
-[[Category: Maryanoff, B.E.]]
+[[Category: Maryanoff, B E.]]
-[[Category: Mathews, F.S.]]
+[[Category: Mathews, F S.]]
-[[Category: Pineda, A.O.]]
+[[Category: Pineda, A O.]]
 [[Category: Sukumar, N.]]
-[[Category: Wells, G.I.]]
+[[Category: Wells, G I.]]
 [[Category: OHH]]
 [[Category: SO4]]
 [[Category: inflammation inhibitor serine protease]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:19:52 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:09:18 2008''