Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A peptidyl carbamate, p-nitrophenyl N-(succinyl-L-alanyl-L-alanyl-L-prolyl-methyl)-N-isopropylcarbamate++ + (PCI) was tested for its ability to inhibit the elastolytic activity of human neutrophil elastase (HNE) and to prevent HNE-induced emphysema and secretory cell metaplasia in the hamster. In vitro, 50% of the elastolytic activity of 10 micrograms of HNE was inhibited by 0.9 micrograms of PCI, a molar ratio of PCI to HNE of 4.5. Bronchoalveolar lavage of hamsters receiving PCI intratracheally showed a rapid decrease in HNE inhibitory activity (4 min for 50% decrease), suggesting rapid clearance, binding, or inactivation of the PCI. Instillation of 300 micrograms of HNE combined with 100, 500, or 3,000 micrograms PCI, a 16-, 83-, and 503-fold molar excess of PCI, respectively (molar ratios of 17, 84, and 504), suppressed HNE-induced lung hemorrhage, but it did not moderate HNE-induced emphysema despite the large molar excess of inhibitor. When PCI was covalently bound to a linear hydrophilic polymer of alpha,beta-poly[N(2-hydroxyethyl)-D,L-aspartamide], producing a polymer-bound carbamate inhibitor (PPCI) of HNE, the time for a 50% decrease of PPCI functional activity from the hamster lung lavage was 421 min. Instillation of 100 micrograms of PPCI 1 h before instillation of 300 micrograms HNE resulted in significant amelioration of emphysema; 900 micrograms of PPCI was required to obtain amelioration of bronchial secretory cell metaplasia. The larger dose of PPCI also provided significant amelioration of emphysema when the interval between PPCI and HNE administration was 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Covalently linking a peptidyl carbamate elastase inhibitor to a hydrophilic polymer increases its effectiveness in preventing emphysema and secretory cell metaplasia in the hamster. 148 40

The design and synthesis of macromolecular peptidyl carbamate inhibitors of human leukocyte elastase (HLE), based on coupling of a low-molecular-weight peptidyl carbamate, succinylalanylalanylprolylmethyl isopropyl carbamate, with a linear hydrophilic polymer, poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide] or poly-alpha-[N5-(2-hydroxyethyl)-L-glutamine], is described. The covalent linkage between a flexible linear polymer and a peptidyl carbamate inhibitor of HLE did not compromise in vitro inhibitory capacity. The macromolecular peptidyl carbamates reported here represent a novel class of elastase inhibitors with a Ki ranging from 35.5 to 2.0 nM.
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PMID:Synthetic macromolecular inhibitors of human leukocyte elastase. 1. Synthesis of peptidyl carbamates bound to water-soluble polymers: poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide] and poly-alpha-[N5-(2-hydroxyethyl)-L-glutamine]. 802 24

Several macromolecular inhibitors of human leukocyte elastase (HLE) were prepared by covalently bonding a low molecular weight HLE inhibitor peptidyl carbamate, p-nitrophenyl-N-[succinyl-L-alanyl-L-ananyl-L-prolylmethyl]- N-isopropyl carbamate 1, with the neutral hydrophilic polymer, poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide], PHEA 2. These novel polymeric compounds differed in the molecular size of their PHEA polymer backbone and the extent of loading of the peptidyl carbamate, (PC). They were shown to efficiently inhibit HLE (Ki = 97 to 12.8 nM) as intact macromolecular entities and were found to be more stable to hydrolysis than the non-polymer bound low molecular weight inhibitor 1. The inhibition of HLE by the novel macromolecular inhibitors was found to be noncompetitive and reversible, proceeding via slow formation of inhibitor-enzyme complex. The effect of loading of 1 and molecular size of the PHEA 2 polymer on enzymatic parameters Ki, kon and koff is discussed and a possible mechanism of inhibition is presented.
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PMID:Synthetic macromolecular inhibitors of human leukocyte elastase. 2. Effect of loading of a peptidyl carbamate inhibitor and molecular size of polymer backbone on its inhibitory capacity. 920 87

Several peptidyl thiocarbamate inhibitors of human leukocyte elastase were synthesized in the molecular weight range of 700-800. Two different sequences with lysine at the P3 and ornithine at the P4 positions were synthesized. Most of the inhibitors with large molecular weights showed high inhibitory capacity with Ki values as low as 10(-8)M. Compounds immobilized on poly,alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide] (PHEA) polymers with an average molecular weight of 36,000 showed higher inhibitory capacity than their free forms.
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PMID:Synthesis and mechanism of action of novel thiocarbamate inhibitors of human leukocyte elastase. 1085 Sep 55

Several peptidyl thiocarbamate inhibitors of human leukocyte elastase were synthesized in the molecular weight range of 700-800. Two different sequences with lysine at the P(3) and ornithine at the P(4) positions were synthesized. Most of the inhibitors with large molecular weights showed high inhibitory capacity with Ki values as low as 10(-8) M. Compounds immobilized on poly,alpha,beta-[N-(2-hydroxyethyl)-d,l-aspartamide] (PHEA) polymers with an average molecular weight of 36,000 showed higher inhibitory capacity than their free forms.
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PMID:Synthesis and Mechanism of Action of Novel Thiocarbamate Inhibitors of Human Leukocyte Elastase. 1093 34

Neutrophil granulocytes are effector cells in innate and humoral immunity. They are involved in inflammatory processes by releasing pro-inflammatory enzymes, such as the human neutrophil elastase (HNE). We here report an optimisation of an HNE release assay using microplates. Special attention has been directed to overcome the often observed activation of neutrophils during isolation from fresh blood. This so-called basal stimulation can take place without addition of external stimulants and can cause severe problems during the assay. We demonstrated that bovine serum albumin (BSA), lipopolysaccharide (LPS), use of different blood donors, heparin and ethylenediaminetetraacetic acid (EDTA) do not cause basal stimulation, but may be due to mechanical stress and the immune system of the blood donor. Here, the number of eosinophils may play a role in the induction of activation. Basal stimulation was overcome when a hypertonic solution, such as sucrose- with N-(2-hydroxyethyl)-piperazine-N'-2-ethanesulfonic acid (HEPES) buffer, was used during centrifugation and the isolated granulocytes were left in phosphate buffered saline (PBS) for 30 min before stimulation. Sesquiterpene lactones (SLs), known for their anti-inflammatory activity were used for evaluation of the assay and were observed to inhibit HNE release at micromolar concentrations. Whereas N-formyl-methionyl-leucylphenylalanine (fMLP), platelet-activating factor (PAF) and basal stimulation resulted in similar IC50 values, phorbol-12-myristate-13-acetate (PMA) as a stimulant needed higher concentrations of SLs. The molecular inhibitory mechanism of SLs is discussed.
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PMID:Optimisation of a human neutrophil elastase assay and investigation of the effect of sesquiterpene lactones. 1609 62