Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human leukocyte elastase (HLE) is a serine protease that contributes to tissue destruction in various disease states-for example, in emphysema. FR901277 is a natural product isolated from the culture filtrate of Streptomyces resistomicificus and is a potent inhibitor of both HLE and porcine pancreatic elastase (PPE). FR901277 consists of four normal amino acids and three unusual amino acids, and is a unique bicyclic peptide compound. The crystal structure of PPE complexed with FR901277 has been determined at 1.6 A resolution. The Ogamma atom of Ser-195 in PPE did not form a covalent bond with FR901277, but formed a hydrogen bond with the Nvarepsilon atom of His-57. On the other hand, the portion from L-Orn(1) through dehydroxyThr(3) in FR901277 formed an antiparallel beta-sheet structure with the backbone of the active site in PPE. The S4 through S2' binding subsites in PPE were all occupied by the hydrophobic side chains of the inhibitor molecule. Especially, the ethylidene moiety of FR901277 occupied the S1 specific pocket, indicating a CH/pi interaction. In addition, the isopropyl side chain of L-Val(7) was located at the enzyme surface between the S2 and S1' pockets with several van der Waals contacts. However, the amino acid (4) residue was not involved in a significant interaction with PPE. Comparison of inhibitor structures in different environments showed that FR901277 has a highly rigid bicyclic framework; however, it can slightly change its conformation according to the circumstances. The binding mode of FR901277 at the active site of PPE was directly applicable to that in HLE, after consideration of induced fit. The structure of the PPE-FR901277 complex provided much information regarding potential sites for modification of the physicochemical properties of FR901277.
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PMID:Structure of porcine pancreatic elastase complexed with FR901277, a novel macrocyclic inhibitor of elastases, at 1.6 A resolution. 1073 4

Human neutrophil elastase (HNE, IEC 3. 4. 21. 37) is a causative factor of inflammatory diseases, including emphysema and rheumatoid arthritis. Enzymatic characterization is important for the development of new drugs involved in the regulation of this enzyme. In this study, we investigated the enzymatic and biochemical properties of five different elastolytic enzymes, with a molecular mass between 24 kDa and 72 kDa. Three elastases, molecular masses of 27, 29, 31 kDa, might be elastase isozymes that have the same NH2-terminal amino acid sequences of Ile-Val-Gly-Gly-Arg-Arg-Ala. The 24-kDa enzyme, which showed the identical NH2-terminal amino acid sequences to elastase, was a degraded fragment of native elastase. The elastolytic activity was conserved at the 6/7 domain of the NH2-terminal region. The inhibitory characteristics of PMSF, DipF were the same as those of native elastases. The 72-kDa molecule, which showed elastolytic activity, might be a trimer formed between native elastases (31 kDa and 29 kDa) and a cathepsin G-like enzyme, which did not show elastolytic activity but enhanced the elastolytic activity of neutrophil elastase. Although this cathepsin G-like enzyme showed weak cathepsin G activity, it has distinguishable NH2-terminal sequences of Ile-Val-Gly-Gly-Ser-Arg-Ala- from those of elastase or cathepsin G. The potentiation of elastolytic activity could be a result of the trimerization of native elastase with a cathepsin G-like enzyme, and was then weakly inhibited by serine protease inhibitors, such as PMSF, DipF. Therefore, we suggest the cathepsin G-like enzyme to be a novel enzyme, which has an important role in the development of inflammation.
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PMID:Enzymatic and molecular biochemical characterizations of human neutrophil elastases and a cathepsin G-like enzyme. 1110 Nov 39

The serine proteinase elastase is located in the azurophil granules of mature circulating polymorphonuclear neutrophils. This neutrophil elastase or NE is a potent non specific serine protease which plays a role as bactericidal agent and in the degradation of immune complexes by intraphagosomal processes. It promotes inflammation when the granule contents are secreted in the extracellular environment. In certain pathological circumstances, an imbalance between NE and its major plasmatic inhibitor alpha 1-PI (formerly, alpha 1-antitrypsin) leads to abnormal tissue destruction and disease development. Genetic or acquired alpha 1-PI deficiency is thought to be involved in the pathogenesis of pulmonary emphysema. A variety of degenerative and degradative disorders are also associated to uncontrolled proteolysis by NE (rheumatoid arthritis, glomerulonephritis, adult respiratory distress symptom, psoriasis, cancer). Numerous inhibitors of NE have been reported. Various molecules are currently undergoing clinical trials for emphysema and other pulmonary diseases.
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PMID:[Elastase inhibitors]. 1172 26

The constant increase of life expectancy is associated with major ageing of developed populations. This indicates that the new century will have one of most epidemic progressions of cardiovascular, cancer and inflammatory diseases. The high challenge for medical research is to compress such morbidity. In these conditions, invertebrates have demonstrated to be truly useful models in drug discovery for such ageing diseases. The last decade, drug discovery in leeches has opened the gate of new molecules to treat emphysema, coagulation, inflammation, dermitis and cancer. Also other invertebrates such as insects, which evolved from the annelids, harvest potential interesting molecules, such as serine protease inhibitors that can be exploited by the medical industry.
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PMID:Trypsin and chymotrypsin inhibitors in insects and gut leeches. 1194 53

Serine proteases (SP), such as thrombin, factor Xa, elastase, trypsin are implicated in many clinical disorders such as emphysema, arthritis and cardiovascular diseases. These enzymes, in normal physiological conditions, are regulated by naturally occurring serine protease inhibitors, such as anti-thrombin III involved in thromb in inhibition. Primitive parasitic invertebrates have co-evolved highly specific mechanisms to communicate with their hosts for survival purposes, by blocking host processes such as blood coagulation. Thus a battery of new powerful molecules from blood-sucker animals acting at different points of the coagulation cascade such like factor Xa, thrombin, platelets aggregation inhibitors have been isolated and are now at a clinical level. In this review, we focus our attention on thrombin inhitors.
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PMID:Leech thrombin inhibitors. 1194 54

Human plasma contains a number of proteinase inhibitors which together form 10% of the total plasma proteins. Serine proteases are a group of closely related proteolytic enzymes, with serine in their active site. These play a key role in coagulation, fibrinolysin, kinin and complement activation. Serine protease inhibitors or "serpins" are specific inhibitors which control the activities of these enzymes. Among the serine protease inhibitors. Alpha-1 antitrypsin (alpha1 ATD) is found in highest concentration in plasma. It is the major physiologic inhibitor for neutrophil elastase. It has control over the elastase mediated degradation of elastic tissue in the lung. Alpha1ATD deficiency is a common genetic disorder and potentially lethal disease predominantly found in North European population--where the incidence is one in 2500; worldwide figures suggest that one in 6000 people have classic alpha1ATD. In cases of deficiency, antielastase activity is reduced in the lungs which results in increased elastin breakdown and development of emphysema. Cigarette smoking contributes to destructive changes in emphysema by suppressing the proteinase inhibitory activity of human serum and by inducing certain bronchoalveolar changes. Prevalence and severity of asthma increases in persons with abnormal alpha1ATD phenotype.
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PMID:Alpha-1 antitrypsin deficiency in emphysema. 1216 15

Abnormal production of matrix metalloproteinases (MMPs) has been observed in a variety of diseases, such as emphysema, atherosclerosis, and cancer metastasis. Destruction of connective tissue ensues and elastin is often a key target. Three of the main elastolytic MMPs are the gelatinases MMP-2 and MMP-9 and the metalloelastase MMP-12. To investigate the possibility of using peptides to inhibit the elastolytic activity of these enzymes, we mapped the sites within tropoelastin recognized by MMP-9 and MMP-12. Peptides that correspond to regions overlapping these sites were then tested for their ability to inhibit these MMPs. These included an unmodified peptide directed against MMP-9 (peptide PP), cysteine-containing peptides that mimicked either the MMP-9 (peptide NCP) or the MMP-12 (peptide lin24) cleavage sites in tropoelastin and their cyclized forms (CP and cyc24, respectively), and a peptide containing a zinc-chelating hydroxamate group directed against MMP-9 (HP). The presence of a free sulfhydryl or hydroxamate group capable of chelating the zinc ion in the active site of the MMPs was generally found to increase the inhibitory activity of the peptides. The specificity of the inhibitors varied, with some of the inhibitors showing activity against all of the MMPs examined. None of the inhibitors had any significant effect on the activity of the unrelated serine protease, plasmin. K(i) values for the inhibitors were in the micromolar range. Our results suggest ways of developing other MMP inhibitors based on substrate recognition sites that may provide greater levels of inhibition.
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PMID:Rational design of tropoelastin peptide-based inhibitors of metalloproteinases. 1250

Cumulative evidence has shown that a delicate balance between serine proteases and their inhibitors is crucial for normal functioning of several biological pathways. The importance of proteases and their inhibitors is well documented in several human diseases. Among them, the best documented are hemophilia B, a genetic deficiency of the serine protease coagulation factor IX and serpinophathies. Alpha-1-antitrypsin deficiency (MIM 107400), is associated with early-onset emphysema and liver disease, while hereditary angioedema (HANE; MIM 106100) is caused by mutations in the C1 inhibitor, a serpin involved in the regulation of the complement cascade. Recently, two human genetic diseases of the central nervous system have been related to mutations in components of extracellular proteolytic systems. Here, we review the recent advances in this field.
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PMID:Extracellular proteases and their inhibitors in genetic diseases of the central nervous system. 1292 75

The ability to inhibit serine proteases is a major focus in the pharmaceutical industry. Serine proteases of medical importance range in phylogenetic diversity from the metallo-proteases, which play a role in pulmonary hypertension, and destruction of the lung parenchyma in emphysema, to those proteases (beta-lactamases), which play a role in the resistance of bacteria to beta-lactam antibiotics. In both the mammalian and microbial systems, the development of serine protease inhibitors has been a focal strategy spurring investigations in the area of serine protease dependent prodrugs that incorporate a bactericidal moiety as well as other classes of metalloprotease inhibitors.
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PMID:The relationship between inhibitors of eukaryotic and prokaryotic serine proteases. 1537 40

Serine proteases are attractive targets for the design of enzyme inhibitors since they are involved in the etiology of several diseases. Within the class of serine proteases, HLE is one of the most destructive enzymes in the body. It is implicated in the promotion or exacerbation of a number of diseases including pancreatitis, acute respiratory syndrome, rheumatoid arthritis, atherosclerosis, pulmonary emphysema, and cystic fibrosis. Thrombin, a trypsin-like serine protease, plays a dual role in thrombogenesis, including fibrin formation and platelet activation. As a result, thrombin constitutes one of the most widely studied targets for antithrombotic strategy. Numerous inhibitors of serine proteases have been reported during the past three decades. Among them, coumarin-type molecules displayed a high inhibitory potency towards various serine proteases. At that time, halomethyl dihydrocoumarins have been shown to behave as the first general suicide inhibitors of serine protease. These molecules inhibit several proteases such as human leucocyte elastase, porcine pancreatic elastase, thrombin, urokinase and human plasmin. Isocoumarins are very effective as mechanism-based inhibitors of serine proteases. Pharmacomodulation on the 3-alkoxy-4-chloroisocoumarins and the 3-alkoxy-7-amino-4-chloroisocoumarins led to strong inhibitors of numerous serine proteases such as HLE, human factor XIa and XIIa, thrombin, urokinase and kallikrein. Recently, a series of coumarins characterised by an alkyl, aryl ester, amide, thioester or ketone in the position 3 and an electrophilic chloromethyl moiety in the position 6 have been developed. These compounds were found to be high inhibitors of alpha-chymotrypin, HLE and human thrombin.
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PMID:Coumarin and isocoumarin as serine protease inhibitors. 1557 71


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