Inhibitors directed to binding domains in neutrophil elastase

Tyagi, Suresh C.; Simon, Sanford R.

doi:10.1021/bi00494a030

Cited by 32 publications

(22 citation statements)

References 55 publications

(56 reference statements)

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“…The mutations in the TIMP-3 gene [40] in patients with Sorsby's fundus dystrophy have been identified. Disruption of connective tissue turnover and the consequent effect on matrix stability has been implicated in a number of diseases [26,32,37], and the role of MMPs has been demonstrated in the ECM/MMP/TIMP family [26,32,33,37]. Collectively, these studies suggested that disruption of MMP-mediated matrix remodeling does affect the composition and function of tissues.…”

Section: Extracellular Matrix Dynamics and Genetic Basis Of Heart Faimentioning

confidence: 95%

Extracellular matrix dynamics in heart failure: A prospect for gene therapy

Tyagi

1998

J. Cell. Biochem.

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In chronic congestive heart failure, an illness affecting more than 4 million Americans, there is impairment of myocardial extracellular matrix (ECM) remodeling. Failing human ventricular myocardium contains activated matrix metalloproteinases (MMPs), which are involved in adverse ECM remodeling. Our studies support the concept that impaired ECM remodeling and MMP activation are, in part, responsible for the cardiac structural deformation and heart failure. There is no known program that has declared its aim the investigation of the role of ECM gene therapy in heart failure. The development of transgenic technology, and emerging techniques for in vivo gene transfer, suggest a strategy for improving cardiac function by overexpressing or downregulation of the ECM components such as MMPs, tissue inhibitor of metalloproteinases (TIMPs), transforming growth factor-beta1 (TGF-beta), decorin, and collagen in cardiomyopathy and heart failure.

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Section: Extracellular Matrix Dynamics and Genetic Basis Of Heart Faimentioning

confidence: 95%

Extracellular matrix dynamics in heart failure: A prospect for gene therapy

Tyagi

1998

J. Cell. Biochem.

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“…Human neutrophil elastase (HNE) can be One of the most important of these proteases is neutrophil activated by high ionic strength (Lestienne and Bieth 1980) ABBREVIATIONS and is inhibited by a number of polyanionic compounds, including negatively charged polysaccharides (Baici and Bradamante 1984) and RNA (Simon et al 1988). Exarnination of the three-dimensional structure of this protease determined by X-ray crystallography indicates that the extended substrate binding cavity contains abundant hydrophobic side chains and, in the vicinity of the subsites SrSS, a positively charged arginine guanidino group (Arg 217) that has been implicated in binding polyanionic inhibitors (Bode et al 1989; Cook and Ternai 1988; Tyagi and Simon 1990). A recent report identified EDTA as an inhibitor of HNE and suggested that the anionic chelator may bind to at least 1 of the 19 arginine residues in the enzyme (Burnett et al 1988).…”

Section: Introductionmentioning

confidence: 99%

Interaction of neutrophil elastase with hydrophobic polyanionic chelators

Tyagi¹,

Simon²

1991

Biochem. Cell Biol.

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The polyanionic calcium chelators, ethylenediamine-tetraacetic acid (EDTA), ethylene-bis-(oxyethylenenitrilo)-tetraacetic acid (EGTA), [bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA), 1-[2-amino-5-(6-carboxyindol-2-yl) phenoxyl]-2-(2'-amino-5'-methylphenoxy)ethane-N,N,N1, N1-tetraacetic acid (INDO-1), 1-[2-(5-carboxyoxazol-2yl)-6-phenoxyl]-2-(2'-amino-5'- methylphenoxy)ethane-N,N,N',N'-tetraacetic acid (FURA-2), and 2-([2-bis-(carboxymethyl)-amino-5-methylphenoxy]-methyl(-6-methyl-8- bis-(bis-(carboxymethyl)-aminoquinoline (QUIN-2), are all inhibitors of amidolytic activity of human neutrophil elastase (HNE). With MeOSuc-Ala-Ala-Pro-Val-pNA as substrate, these chelators all display mixed partial competitive and partial noncompetitive inhibition, but with the smaller substrate, pGlu-Pro-Val-pNA, only the noncompetitive component persists. The most effective inhibitor is FURA-2, with an apparent Ki of 0.5-0.7 mM. QUIN-2 is somewhat less effective, with a Ki of 2 mM, while EDTA is much less effective, with a Ki of 7 mM. In general, the more hydrophobic chelators are the best inhibitors, although INDO-1, which is about the same size as FURA-2, is surprisingly ineffective as an inhibitor. The chelators no longer function as effective inhibitors if their carboxyl groups are blocked by esterification with acetoxymethyl groups or by complexation with calcium ions, indicating that their binding to HNE is mediated in part through electrostatic interactions with a center of positive charge on the protein.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The mutations in the TIMP-3 gene [Weber et al, 19941 in patients with Sorsby's fundus dystrophy have been identified. Disruption of connective tissue turnover and the consequent effect on matrix stability has been implicated in a number of diseases [Tyagi and Simon, 1990;Tyagi et al, 1995b, and the role of MMPs has been demonstrated in the ECM/MMP/TIMP family [Tyagi et al, 1995b. Collectively, these studies suggested that disruption of MMP-mediated matrix remodeling does affect the composition and function of tissues.…”

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confidence: 99%

Differential gene expression of extracellular matrix components in dilated cardiomyopathy

et al. 1996

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Extracellular matrix metalloproteinases (MMPs) are activated in dilated cardiomyopathic (DCM) hearts [Tyagi et al. (1996): Mol Cell Biochem 155:13-21]. To examine whether the MMP activation is occurring at the gene expression level, we performed differential display mRNA analysis on tissue from six dilated cardiomyopathy (DCM) explanted and five normal human hearts. Specifically, we identified three genes to be induced and several other genes to be repressed following DCM. Southern blot analysis of isolated cDNA using a collagenase cDNA probe indicated that one of the genes induced during DCM was interstitial collagenase (MMP-1). Northern blot analysis using MMP-1 cDNA probe indicated that MMP-1 was induced three- to fourfold in the DCM heart as compared to normal tissue. To analyze posttranslational expression of MMP and tissue inhibitor of matrix metalloproteinase (TIMP) we performed immunoblot, immunoassay, and substrate zymographic assays. TIMP-1 and MMP-1 levels were 37 +/- 8 ng/mg and 9 +/- 2 ng/mg in normal tissue specimens (P < 0.01) and 2 +/- 1 ng/mg and 45 +/- 11 ng/mg in DCM tissue (P < 0.01), respectively. Zymographic analysis demonstrated lytic bands at 66 kDa and 54 kDa in DCM tissue as compared to one band at 66 kDa in normal tissue. Incubation of zymographic gel with metal chelator (phenanthroline) abolished both bands suggesting activation of neutral MMP in DCM heart tissue. TIMP-1 was repressed approximately twentyfold in DCM hearts when compared with normal heart tissue. In situ immunolabeling of MMP-1 indicated phenotypic differences in the fibroblast cells isolated from the DCM heart as compared to normal heart. These results suggest disruption in the balance of myopathic-fibroblast cell ECM-proteinase and antiproteinase in ECM remodeling which is followed by dilated cardiomyopathy.

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Inhibitors directed to binding domains in neutrophil elastase

Cited by 32 publications

References 55 publications

Extracellular matrix dynamics in heart failure: A prospect for gene therapy

Extracellular matrix dynamics in heart failure: A prospect for gene therapy

Interaction of neutrophil elastase with hydrophobic polyanionic chelators

Differential gene expression of extracellular matrix components in dilated cardiomyopathy

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