Relevant bibliographies by topics / Serine protease inhibitor

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Academic literature on the topic 'Serine protease inhibitor'

Author: Grafiati
Published: 4 June 2021
Last updated: 20 February 2023

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Journal articles on the topic "Serine protease inhibitor"

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Mitchell, Angela M., and R. Jude Samulski. "Mechanistic Insights into the Enhancement of Adeno-Associated Virus Transduction by Proteasome Inhibitors." Journal of Virology 87, no. 23 (September 11, 2013): 13035–41. http://dx.doi.org/10.1128/jvi.01826-13.

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Proteasome inhibitors (e.g., bortezomib, MG132) are known to enhance adeno-associated virus (AAV) transduction; however, whether this results from pleotropic proteasome inhibition or off-target serine and/or cysteine protease inhibition remains unresolved. Here, we examined recombinant AAV (rAAV) effects of a new proteasome inhibitor, carfilzomib, which specifically inhibits chymotrypsin-like proteasome activity and no other proteases. We determined that proteasome inhibitors act on rAAV through proteasome inhibition and not serine or cysteine protease inhibition, likely through positive changes late in transduction.
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Avanzo, Petra, Jerica Sabotič, Sabina Anžlovar, Tatjana Popovič, Adrijana Leonardi, Roger H. Pain, Janko Kos, and Jože Brzin. "Trypsin-specific inhibitors from the basidiomycete Clitocybe nebularis with regulatory and defensive functions." Microbiology 155, no. 12 (December 1, 2009): 3971–81. http://dx.doi.org/10.1099/mic.0.032805-0.

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We have isolated serine protease inhibitors from the basidiomycete Clitocybe nebularis, CnSPIs, using trypsin affinity chromatography. Full-length gene and cDNA sequences were determined for one of them, named cnispin, and the recombinant protein was expressed in Escherichia coli at high yield. The primary structure and biochemical properties of cnispin are very similar to those of the Lentinus edodes serine protease inhibitor, until now the only member of the I66 family of protease inhibitors in the MEROPS classification. Cnispin is highly specific towards trypsin, with K i in the nanomolar range. It also exhibited weaker inhibition of chymotrypsin and very weak inhibition of subtilisin and kallikrein; other proteases were not inhibited. Inhibitory activity against endogenous proteases from C. nebularis revealed a possible regulatory role for CnSPIs in the endogenous proteolytic system. Another possible biological function in defence against predatory insects was indicated by the deleterious effect of CnSPIs on the development of larvae of Drosophila melanogaster. These findings, together with the biochemical and genetic characterization of cnispin, suggest a dual physiological role for this serine protease inhibitor of the I66 MEROPS family.
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Hudig, D., N. J. Allison, T. M. Pickett, U. Winkler, C. M. Kam, and J. C. Powers. "The function of lymphocyte proteases. Inhibition and restoration of granule-mediated lysis with isocoumarin serine protease inhibitors." Journal of Immunology 147, no. 4 (August 15, 1991): 1360–68. http://dx.doi.org/10.4049/jimmunol.147.4.1360.

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Abstract To kill other cells, lymphocytes can exocytose granules that contain serine proteases and pore-forming proteins (perforins). We report that mechanism-based isocoumarin inhibitors inhibited the proteases and inactivated lysis. When inhibited proteases were restored, lysis was also restored, indicating that the proteases were essential for lysis. We found three new lymphocyte protease activities, "Asp-ase,"Met-ase," and "Ser-ase," which in addition to ly-tryptase and ly-chymase, comprise five different protease activities in rat RNK-16 granules. The general serine protease inhibitor 3,4-dichloroisocoumarin (DCI) inhibited all five protease activities. Essentially all protease molecules were inactivated by DCI before lysis was reduced, as determined from DCI's second order inhibition rate constants for the proteases, the DCI concentrations, and the times of pretreatment needed to block lysis. The pH favoring DCI inhibition of lysis was the pH optimum for protease activity. Isocoumarin reagents acylate, and may sometimes secondarily alkylate, serine protease active sites. Granule proteases, inhibited by DCI acylation, were deacylated with hydroxylamine, restoring both the protease and lytic activities. Hydroxylamine does not restore alkylated proteases and did not restore the lytic activities after inhibition with 4-chloro-7-guanidino-3-(2-phenylethoxy)-isocoumarin, a more alkylating mechanism-based inhibitor designed to react with tryptases. It is improbable that isocoumarin reagents directly inactivated pore-forming proteins because 1) these reagents require protease activation, 2) their nonspecific effects are alkylating, and 3) alkylated proteins are not restored by hydroxylamine. We conclude that serine proteases participate in lysis when lysis is mediated by the complete assembly of granule proteins.
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Azouz, Nurit P., Andrea Klingler, Victoria Callahan, Ivan Akhrymuk, Katarina Elez, Lluís Raich, Brandon Henry, et al. "Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2." Pathogens and Immunity 6, no. 1 (April 26, 2021): 55–74. http://dx.doi.org/10.20411/pai.v6i1.408.

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Background: Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry. Methods: We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems. Results: We identified the human extracellular serine protease inhibitor (serpin) alpha 1 antitrypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity. Conclusions: Our data support the key role of extracellular serine proteases in SARS CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.
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Woodard, S. L., D. S. Jackson, A. S. Abuelyaman, J. C. Powers, U. Winkler, and D. Hudig. "Chymase-directed serine protease inhibitor that reacts with a single 30-kDa granzyme and blocks NK-mediated cytotoxicity." Journal of Immunology 153, no. 11 (December 1, 1994): 5016–25. http://dx.doi.org/10.4049/jimmunol.153.11.5016.

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Abstract Cytotoxic NK and T lymphocytes kill virally infected cells within minutes without causing damage to themselves or bystander cells. One mechanism of killing involves exocytosis of granules containing serine proteases and perforin. Serine protease inhibitors block killing of target cells mediated by the cytotoxic lymphocytes. There are at least five different serine protease activities in cytolytic granules. Ten different serine protease sequences have been identified with the use of cDNA-specific clones. It is not known whether only one or several of these serine proteases are essential for cytolytic activity. In this study we show that an irreversible serine protease inhibitor, biotinyl-Aca-Aca-Phe-Leu-PheP(OPh)2, selectively inhibits a chymotrypsin-like (chymase) serine protease activity of rat RNK-16 granule extracts. Under the same conditions, only one 30-kDa (reduced) band was detected on protein blots. Furthermore, only one of three chymase peaks separated by hydrophobic interaction chromatography was inhibited. When this granzyme was inhibited, granule-mediated lysis of erythrocytes was diminished. NK cell killing was completely blocked when biotinyl-Aca-Aca-Phe-Leu-PheP(OPh)2 was added to cytotoxicity assays at 200 microM with rat splenocytes as effectors. By confocal fluorescence microscopy, we show that this inhibitor localizes to distinct regions within RNK-16 cells and rat NK cells. Inhibitor treatment of intact cells inactivated the chymase activity and reduced lysis found in their dense organelles. Together these data indicate that biotinyl-Aca-Aca-Phe-Leu-PheP(OPh)2 inhibits a granule chymase that is essential to cytolytic activity of NK cells.
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Brüning, Mareke, Martina Lummer, Caterina Bentele, Marcel M. W. Smolenaars, Kees W. Rodenburg, and Hermann Ragg. "The Spn4 gene from Drosophila melanogaster is a multipurpose defence tool directed against proteases from three different peptidase families." Biochemical Journal 401, no. 1 (December 11, 2006): 325–31. http://dx.doi.org/10.1042/bj20060648.

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By alternative use of four RSL (reactive site loop) coding exon cassettes, the serpin (serine protease inhibitor) gene Spn4 from Drosophila melanogaster was proposed to enable the synthesis of multiple protease inhibitor isoforms, one of which has been shown to be a potent inhibitor of human furin. Here, we have investigated the inhibitory spectrum of all Spn4 RSL variants. The analyses indicate that the Spn4 gene encodes inhibitors that may inhibit serine proteases of the subtilase family (S8), the chymotrypsin family (S1), and the papain-like cysteine protease family (C1), most of them at high rates. Thus a cohort of different protease inhibitors is generated simply by grafting enzyme-adapted RSL sequences on to a single serpin scaffold, even though the target proteases contain different types and/or a varying order of catalytic residues and are descendents of different phylogenetic lineages. Since all of the Spn4 RSL isoforms are produced as intracellular residents and additionally as variants destined for export or associated with the secretory pathway, the Spn4 gene represents a versatile defence tool kit that may provide multiple antiproteolytic functions.
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Hong, Tran Thi, Ton That Huu Dat, Nguyen Phuong Hoa, Tran Thi Kim Dung, Vu Thi Thu Huyen, Le Minh Bui, Nguyen Thi Kim Cuc, and Pham Viet Cuong. "Expression and characterization of a new serine protease inhibitory protein in Escherichia coli." Biomedical Research and Therapy 7, no. 2 (February 29, 2020): 3633–44. http://dx.doi.org/10.15419/bmrat.v7i2.590.

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Introduction: Proteases are enzymes that catalyze the hydrolysis of peptide bonds and play an important role in almost all biological processes. However, excessive protein proteolysis can be implicated in several diseases, such as cancer, as well as cardiovascular, inflammatory, neurodegenerative, bacterial, viral and parasitic diseases. In these cases, protease inhibitors can be used as one of versatile tools for regulating proteolytic activity of target proteases as well as therapeutic applications. In this study, we expressed and characterized a new serine protease inhibitory protein (PI-QT) from the metagenome of sponge-associated microorganisms in Escherichia coli. Methods: The gene PI-QT encoding for a new serine protease inhibitory protein was expressed in E. coli BL21(DE3). In addition, the expressed protein was purified and characterized. Results: Optimization of expression of the recombinant protein PI-QT in E. coli showed that suitable conditions for expression of the protein were pre-induction cell density (OD600) of 0.6 - 0.7, IPTG concentration of 1 mM and temperature of 25oC. The protease inhibitory protein was also purified and identified by mass spectrometry LC-MS/MS. The recombinant protein showed inhibitory activity against trypsin anda-chymotrypsin with activity values of 97526 U/mg and 41714 U/mg, respectively. Maximum activity of the protease inhibitory protein was obtained at pH 7 and temperature 20-35oC. The inhibitor was stable over pH 4-9 and up to temperature 50oC. Addition of Zn2+, Mg2+ and Ca2+ enhanced inhibitory activity, whereas other metal ions, surfactants and oxidants reduced inhibitory activity of the protease inhibitor. Conclusion: The recombinant protein PI-QT is a potential protease inhibitor for therapeutic applications.
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Cornwall, Gail A., Angus Cameron, Iris Lindberg, Daniel M. Hardy, Nathaly Cormier, and Nelson Hsia. "The Cystatin-Related Epididymal Spermatogenic Protein Inhibits the Serine Protease Prohormone Convertase 2." Endocrinology 144, no. 3 (March 1, 2003): 901–8. http://dx.doi.org/10.1210/en.2002-220997.

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The cystatin-related epididymal spermatogenic (CRES) protein is related to the family 2 cystatins of the cystatin superfamily of cysteine protease inhibitors. However, CRES lacks sequences important for cysteine protease inhibitory activity and is specifically expressed in reproductive and neuroendocrine tissues. Thus, CRES is distinct from cystatins and may perform unique tissue-specific functions. The purpose of the present study was to determine whether CRES functions as a protease inhibitor in in vitro assays. In contrast to mouse recombinant cystatin C, recombinant CRES did not inhibit the cysteine proteases papain and cathepsin B, suggesting that it probably does not function as a typical cystatin. CRES, however, inhibited the serine protease prohormone convertase 2 (PC2), a protease involved in prohormone processing in the neuroendocrine system, whereas cystatin C showed no inhibition. CRES did not inhibit subtilisin, trypsin, or the convertase family members, PC1 and furin, indicating that it selectively inhibits PC2. Kinetic analysis showed that CRES is a competitive inhibitor of PC2 with a Ki of 25 nm. The removal of N-terminal sequences from CRES decreased its affinity for PC2, suggesting that the N terminus may be important for CRES to function as an inhibitor. These studies suggest that CRES is a cross-class inhibitor that may regulate proprotein processing within the reproductive and neuroendocrine systems.
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Yoo Im, Sonia, Camila Ramalho Bonturi, Adriana Miti Nakahata, Clóvis Ryuichi Nakaie, Arnildo Pott, Vali Joana Pott, and Maria Luiza Vilela Oliva. "Differences in the Inhibitory Specificity Distinguish the Efficacy of Plant Protease Inhibitors on Mouse Fibrosarcoma." Plants 10, no. 3 (March 23, 2021): 602. http://dx.doi.org/10.3390/plants10030602.

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Metastasis, the primary cause of death from malignant tumors, is facilitated by multiple protease-mediated processes. Thus, effort has been invested in the development of protease inhibitors to prevent metastasis. Here, we investigated the effects of protease inhibitors including the recombinant inhibitors rBbKI (serine protease inhibitor) and rBbCI (serine and cysteine inhibitor) derived from native inhibitors identified in Bauhinia bauhinioides seeds, and EcTI (serine and metalloprotease inhibitor) isolated from the seeds of Enterolobium contortisiliquum on the mouse fibrosarcoma model (lineage L929). rBbKI inhibited 80% of cell viability of L929 cells after 48 h, while EcTI showed similar efficacy after 72 h. Both inhibitors acted in a dose and time-dependent manner. Conversely, rBbCI did not significantly affect the viability of L929 cells. Confocal microscopy revealed the binding of rBbKI and EcTI to the L929 cell surface. rBbKI inhibited approximately 63% of L929 adhesion to fibronectin, in contrast with EcTI and rBbCI, which did not significantly interfere with adhesion. None of the inhibitors interfered with the L929 cell cycle phases. The synthetic peptide RPGLPVRFESPL-NH2, based on the BbKI reactive site, inhibited 45% of the cellular viability of L929, becoming a promising protease inhibitor due to its ease of synthesis.
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Ó Cuív, Páraic, Rajesh Gupta, Hareshwar P. Goswami, and Mark Morrison. "Extending the Cellulosome Paradigm: the Modular Clostridium thermocellum Cellulosomal Serpin PinA Is a Broad-Spectrum Inhibitor of Subtilisin-Like Proteases." Applied and Environmental Microbiology 79, no. 19 (July 19, 2013): 6173–75. http://dx.doi.org/10.1128/aem.01912-13.

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ABSTRACTClostridium thermocellumencodes a cellulosomal, modular, and thermostable serine protease inhibitor (serpin), PinA. PinA stability but not inhibitory activity is affected by the Fn(III) and Doc(I) domains, and PinA is a broad inhibitor of subtilisin-like proteases and may play a key role in protecting the cellulosome from protease attack.
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Dissertations / Theses on the topic "Serine protease inhibitor"

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Gariani, Talal. "Design of serine protease inhibitor peptides." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267244.

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Combe, Caroline Jane. "Hepatic receptor(s) for serine protease-inhibitor complexes." Thesis, University of Aberdeen, 1995. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU549619.

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A number of questions about the hepatic mechanisms of tissue-type plasminogen activator (t-PA) clearance still remain unanswered. Although certain liver endothelial cell receptors have been implicated, the parenchymal cell system, which is responsible for most clearance, still remains a mystery. The aim of this project, in the most simple terms, was to solve this mystery. The foundation upon which this project was built was that t-PA is cleared, by a hepatic receptor, in complex with its primary inhibitor, plasminogen activator inhibitor type 1 (PAI-1). The affinity of binding was estimated to be 0.8-1.0 nM and the number of binding sites per cell, 35 000-70 000. Affinity chromatography and chemical cross-linking resulted in a band of A?70 kDa which was presumed to be the receptor. This project was designed to characterize this hepatic receptor for t-PA-PAI-1 and determine whether plasmin-2-antiplasmin (PAP) is recognised by the same receptor. Characterizing the receptor was attempted initially by employing cell binding assays using the human hepatoma cell line, Hep G2. This methodology required the formation and characterization of pure pre-formed ligands which was achieved by overcoming preliminary problems. The binding assays showed that competition between t-PA-PAI-1 and PAP was occurring but that high non-specific binding and error between duplicate samples suggested that this system was not suitable for characterization of the receptor. The data accumulated in this study suggested that LRP was primarily responsible for hepatic uptake of t-PA and that proteases were recognised preferentially in complex with their inhibitors.
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Swedberg, Joakim Erik. "Rational design of serine protease inhibitors." Thesis, Queensland University of Technology, 2011. https://eprints.qut.edu.au/48131/1/Joakim_Swedberg_Thesis.pdf.

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Proteases regulate a spectrum of diverse physiological processes, and dysregulation of proteolytic activity drives a plethora of pathological conditions. Understanding protease function is essential to appreciating many aspects of normal physiology and progression of disease. Consequently, development of potent and specific inhibitors of proteolytic enzymes is vital to provide tools for the dissection of protease function in biological systems and for the treatment of diseases linked to aberrant proteolytic activity. The studies in this thesis describe the rational design of potent inhibitors of three proteases that are implicated in disease development. Additionally, key features of the interaction of proteases and their cognate inhibitors or substrates are analysed and a series of rational inhibitor design principles are expounded and tested. Rational design of protease inhibitors relies on a comprehensive understanding of protease structure and biochemistry. Analysis of known protease cleavage sites in proteins and peptides is a commonly used source of such information. However, model peptide substrate and protein sequences have widely differing levels of backbone constraint and hence can adopt highly divergent structures when binding to a protease’s active site. This may result in identical sequences in peptides and proteins having different conformations and diverse spatial distribution of amino acid functionalities. Regardless of this, protein and peptide cleavage sites are often regarded as being equivalent. One of the key findings in the following studies is a definitive demonstration of the lack of equivalence between these two classes of substrate and invalidation of the common practice of using the sequences of model peptide substrates to predict cleavage of proteins in vivo. Another important feature for protease substrate recognition is subsite cooperativity. This type of cooperativity is commonly referred to as protease or substrate binding subsite cooperativity and is distinct from allosteric cooperativity, where binding of a molecule distant from the protease active site affects the binding affinity of a substrate. Subsite cooperativity may be intramolecular where neighbouring residues in substrates are interacting, affecting the scissile bond’s susceptibility to protease cleavage. Subsite cooperativity can also be intermolecular where a particular residue’s contribution to binding affinity changes depending on the identity of neighbouring amino acids. Although numerous studies have identified subsite cooperativity effects, these findings are frequently ignored in investigations probing subsite selectivity by screening against diverse combinatorial libraries of peptides (positional scanning synthetic combinatorial library; PS-SCL). This strategy for determining cleavage specificity relies on the averaged rates of hydrolysis for an uncharacterised ensemble of peptide sequences, as opposed to the defined rate of hydrolysis of a known specific substrate. Further, since PS-SCL screens probe the preference of the various protease subsites independently, this method is inherently unable to detect subsite cooperativity. However, mean hydrolysis rates from PS-SCL screens are often interpreted as being comparable to those produced by single peptide cleavages. Before this study no large systematic evaluation had been made to determine the level of correlation between protease selectivity as predicted by screening against a library of combinatorial peptides and cleavage of individual peptides. This subject is specifically explored in the studies described here. In order to establish whether PS-SCL screens could accurately determine the substrate preferences of proteases, a systematic comparison of data from PS-SCLs with libraries containing individually synthesised peptides (sparse matrix library; SML) was carried out. These SML libraries were designed to include all possible sequence combinations of the residues that were suggested to be preferred by a protease using the PS-SCL method. SML screening against the three serine proteases kallikrein 4 (KLK4), kallikrein 14 (KLK14) and plasmin revealed highly preferred peptide substrates that could not have been deduced by PS-SCL screening alone. Comparing protease subsite preference profiles from screens of the two types of peptide libraries showed that the most preferred substrates were not detected by PS SCL screening as a consequence of intermolecular cooperativity being negated by the very nature of PS SCL screening. Sequences that are highly favoured as result of intermolecular cooperativity achieve optimal protease subsite occupancy, and thereby interact with very specific determinants of the protease. Identifying these substrate sequences is important since they may be used to produce potent and selective inhibitors of protolytic enzymes. This study found that highly favoured substrate sequences that relied on intermolecular cooperativity allowed for the production of potent inhibitors of KLK4, KLK14 and plasmin. Peptide aldehydes based on preferred plasmin sequences produced high affinity transition state analogue inhibitors for this protease. The most potent of these maintained specificity over plasma kallikrein (known to have a very similar substrate preference to plasmin). Furthermore, the efficiency of this inhibitor in blocking fibrinolysis in vitro was comparable to aprotinin, which previously saw clinical use to reduce perioperative bleeding. One substrate sequence particularly favoured by KLK4 was substituted into the 14 amino acid, circular sunflower trypsin inhibitor (SFTI). This resulted in a highly potent and selective inhibitor (SFTI-FCQR) which attenuated protease activated receptor signalling by KLK4 in vitro. Moreover, SFTI-FCQR and paclitaxel synergistically reduced growth of ovarian cancer cells in vitro, making this inhibitor a lead compound for further therapeutic development. Similar incorporation of a preferred KLK14 amino acid sequence into the SFTI scaffold produced a potent inhibitor for this protease. However, the conformationally constrained SFTI backbone enforced a different intramolecular cooperativity, which masked a KLK14 specific determinant. As a consequence, the level of selectivity achievable was lower than that found for the KLK4 inhibitor. Standard mechanism inhibitors such as SFTI rely on a stable acyl-enzyme intermediate for high affinity binding. This is achieved by a conformationally constrained canonical binding loop that allows for reformation of the scissile peptide bond after cleavage. Amino acid substitutions within the inhibitor to target a particular protease may compromise structural determinants that support the rigidity of the binding loop and thereby prevent the engineered inhibitor reaching its full potential. An in silico analysis was carried out to examine the potential for further improvements to the potency and selectivity of the SFTI-based KLK4 and KLK14 inhibitors. Molecular dynamics simulations suggested that the substitutions within SFTI required to target KLK4 and KLK14 had compromised the intramolecular hydrogen bond network of the inhibitor and caused a concomitant loss of binding loop stability. Furthermore in silico amino acid substitution revealed a consistent correlation between a higher frequency of formation and the number of internal hydrogen bonds of SFTI-variants and lower inhibition constants. These predictions allowed for the production of second generation inhibitors with enhanced binding affinity toward both targets and highlight the importance of considering intramolecular cooperativity effects when engineering proteins or circular peptides to target proteases. The findings from this study show that although PS-SCLs are a useful tool for high throughput screening of approximate protease preference, later refinement by SML screening is needed to reveal optimal subsite occupancy due to cooperativity in substrate recognition. This investigation has also demonstrated the importance of maintaining structural determinants of backbone constraint and conformation when engineering standard mechanism inhibitors for new targets. Combined these results show that backbone conformation and amino acid cooperativity have more prominent roles than previously appreciated in determining substrate/inhibitor specificity and binding affinity. The three key inhibitors designed during this investigation are now being developed as lead compounds for cancer chemotherapy, control of fibrinolysis and cosmeceutical applications. These compounds form the basis of a portfolio of intellectual property which will be further developed in the coming years.
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Wångsell, Fredrik. "Design and Synthesis of Serine and Aspartic Protease Inhibitors." Licentiate thesis, Linköping University, Linköping University, Organic Chemistry, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-7372.

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This thesis describes the design and synthesis of compounds that are

intended to inhibit serine and aspartic proteases. The first part of the text deals with preparation of inhibitors of the hepatitis C virus (HCV) NS3 serine protease. Hepatitis C is predominantly a chronic disease that afflicts about 170 million people worldwide. The NS3 protease, encoded by HCV, is essential for replication of the virus and has become one of the main targets when developing drugs to fight HCV. The inhibitors discussed here constitute surrogates for the widely used N-acyl-hydroxyproline isostere designated 4-hydroxy-cyclopentene. The stereochemistry of the 4-hydroxy-cyclopentene scaffold was determined by nuclear overhauser effect spectroscopy (NOESY) and the regiochemistry by heteronuclear multiple bond correlation (HMBC). The scaffold was decorated with different substituents to obtain both linear and macrocyclic HCV NS3 protease inhibitors that display low nanomolar activity. The second part of the thesis describes the design and synthesis of potential aspartic protease inhibitors. The hydroxyethylene motif was used as a noncleavable transition state isostere. The synthetic route yielded a pivotal intermediate with excellent stereochemical control, which was corroborated by NOESY experiments. This intermediate can be diversified with different substituents to furnish novel aspartic protease inhibitors.


Report code: LIU-TEK-LIC-2006:45
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Poliakov, Anton. "Peptide-Based Inhibitors of Hepatitis C Virus NS3 Serine Protease: Kinetic Aspects and Inhibitor Design." Doctoral thesis, Uppsala universitet, Institutionen för naturvetenskaplig biokemi, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4127.

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Hepatitis C is a serious disease that affects about 200 million people worldwide. No anti-HCV vaccine or specific anti-viral drugs are available today. Non-structural protein 3 (NS3) of HCV is a bifunctional serine protease/helicase, and the protease has become a prime target in the search for anti-HCV drugs. In this work, the complete HCV NS3 gene has been cloned and expressed, and the protein has been purified using affinity chromatography. An assay for measuring the protease activity of full-length NS3 protease has been developed and used for inhibition studies. A series of peptide-based inhibitors of NS3 protease varying in length, the composition of the side-chain and the N- and C-terminal groups have been studied. Potent tetra-, penta- and hexapeptide inhibitors of the NS3 protease were discovered. Hexapeptides with an acyl sulfonamide C-terminal residue were the most potent inhibitors of the NS3 protease, having nanomolar Ki-values. The selectivity of the inhibitors was assessed using other serine and cysteine proteases. NS3 protease inhibitors with electrophilic C-terminal groups were non-selective while those comprising a C-terminal carboxylate or acyl sulfonamide group were selective. All inhibitors with a small hydrophobic P1 side-chain residue were non-selective for the NS3 protease, being good inhibitors of human leukocyte elastase. This result highlights the importance of the P1 residue for inhibitor selectivity, which stems from the major role of this residue in determining substrate specificity of serine proteases. Electrophilic inhibitors often cause slow-binding inhibition of serine and cysteine proteases. This was observed with other proteases used in our work but not with NS3 protease, which indicates that mechanism of inhibition of NS3 protease by electrophilic inhibitors may not involve formation of a covalent bond. The structure-activity relationships obtained in this work can be used for improvement of peptide-based inhibitors of HCV NS3 protease towards higher inhibitory potency and selectivity.
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Reinhard, Eva. "Cell and tissue localization of glia derived nexin, a serine protease inhibitor /." [S.l.] : [s.n.], 1989. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=9040.

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Eriksson, Röhnisch Kajsa. "Purification and Technical Application of a Serine Protease Inhibitor from Solanum tuberosum." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-275284.

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elMasry, Nadia Farida. "Folding studies on mutants of Chymotrypsin Inhibitor 2." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309338.

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Forney, John Russell. "Interaction of the Human Serine Protease Inhibitor Alpha-1-antitrypsin with Cryptosporidium parvum." DigitalCommons@USU, 1997. https://digitalcommons.usu.edu/etd/3961.

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The human serine protease inhibitor (serpin) alpha-1-antitrypsin (AAT) was studied for potential interaction with components of the protozoan parasite Cryptosporidium parvum. A homogenate prepared from C. parvum oocysts was incubated with purified human AAT, and complexes formed between the serpin and components of the homogenate were detected using an enzyme-linked immunosorbent assay (ELISA). Serpin:parasite infections were effectively blocked by preincubating AAT with a cognate target enzyme, porcine pancreatic elastase, prior to performing the ELISA on the homogenate. Incubation of a mixture of C. parvum oocysts and sporozoites with AAT demonstrated preferential fluorescence labeling of the sporozoite surface membrane by indirect immunofluorescence assay. Localization of serpin complexes on sporozoites was confirmed by immunogold electron microscopy. AAT was evaluated for in vitro anticryptosporidial activity in a bovine fallopian tube epithelial (BFTE) cell culture system using both oocysts and filter purified sporozoites as inocula. Serial dilutions of AAT were mixed with oocysts (or sporozites) and used to inoculate BFTE cell monolayers. Inoculted cells were maintained at 37ºC/5% CO2 and collected at 24-,48-,72-, and 96-hr post-inoculation intervals. The addition of AAT and other select protease inhibitors (i.e.,antipain, aprotinin, leupeptin, soybean trypsin inhibitor, and phenylmethylsulfonyl floride) significantly inhibited parasite infection (P<0.01) in a concentration- and time-dependent manner when bleach-decontaminated oocysts were used in the inoculum. The anticryptosporidial activity of AAT is postulated to be linked to an antagonistic effect on oocyst excystation and, putatively, the forced expenditure of bioenergetic reserves prior to host cell invasion. This postulate was supported by the observations that serpin activity had no statistically significant effect on reducing established in vitro infections (i.e., 24 hr post-inoculation prior to addition of AAT) and did not inhibit infection of BFTE cells when inoculted with sporozoite preparations. The combined application of AAT and the aminoglycoside paromomycin demonstrated a synergistic anticryptosporidial effect on in vitro infection and suggested the basis for a multi-agent therapeutic protocol in preventing cryptosporidosis. These studies collectively demonstrated an inticryptosporidial potential for serine protease inhibitors, in particular for AAT, and suggest an alternative approach to conventional therapeutic strategies.
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Ferreira, Graziele Cristina. "Purificação e caracterização de um inibidor de elastase de neutrófilos do feijão-caupi (Vigna unguiculata L Walp)." reponame:Repositório Institucional da UFABC, 2017.

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Orientador: Prof. Dr. Sergio Daishi Sasaki
Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biossistemas, 2017.
O Feijão Caupi (Vigna unguiculata (L.) Walp) é uma leguminosa com importante representatividade econômica e nutricional, especialmente no Brasil. Inibidores de serino proteases, como a tripsina, já foram descritos na espécie, assim como em outras plantas. No entanto, nesta espécie, ainda não foram identificados inibidores que apresentem atividade sobre a elastase de neutrófilos humana (HNE), protease envolvida em muitos processos patológicos, como na instalação e progressão da doença pulmonar obstrutiva crônica (DPOC). Nesse estudo, purificamos um inibidor a partir do extrato protéico de Vigna unguiculata que apresenta atividade sobre HNE. Inicialmente, foi realizado o processo de extração alcalina de proteínas, seguido de três passos cromatográficos distintos, utilizando as colunas Hitrap-Q (Troca-iônica), Source15RPC (Fase-Reversa) e ACE18 (Fase-Reversa). Essas etapas foram acompanhadas por testes de atividade inibitória, utilizando os substratos fluorogênicos Meo-Suc-Ala-Ala-Pro-Val-MCA (Elastase) e Z-Phe-Arg-MCA (Tripsina), além de ensaios da quantificação de concentração total de proteínas. Para determinar a massa do inibidor, foram utilizadas as técnicas de espectrometria de massa por MALDI-TOF e SDS-PAGE, o inibidor apresenta massa molecular de 10,99 KDa. O Ki para HNE foi determinado no valor de 9 pM. O inibidor não apresentou atividade inibitória sobre tripsina e trombina, porém foi observada atividade sobre subtilisina e quimotripsina. Estes dados indicam que o inibidor purificado trata-se de uma molécula ainda não caracterizada, devido às suas atividades inibitórias o nomeamos de Vigna unguiculata Elastase Inhibitor (VuEI).
The cowpea (Vigna unguiculata (L.) Walp) is a legume of important economic and nutritional representativeness, especially in Brazil. Serine protease inhibitors, such as trypsin, have been described in many species, as well as in other plants. In this specie an inhibitor with activity on human neutrophil elastase (HNE) has not yet been identified. This protease is involved in many pathological processes, such as the onset and progression of chronic obstructive pulmonary disease (COPD). We purified and characterized an inhibitor from the protein extract of Vigna unguiculata presenting activity towards HNE. Firstly, we performed the alkaline extraction procedure for proteins followed by three different chromatographic steps using Hitrap Q (ion exchange), Source15RPC (Reversed-Phase) and ACE18 (Reversed Phase) columns. These steps were followed by the inhibitory activity tests using fluorogenic substrates, MeO-Suc-Ala-Ala-Pro-Val-MCA (elastase) and Z-Phe-Arg-MCA (trypsin), and quantitation assays of protein concentration. To determinate the size of the molecule, we used MALDI-TOF mass spectrometry and SDS-PAGE. The molecular mass of the inhibitor was 10,99 kDa. The dissociation constant (Ki) toward HNE was 9 pM. HNE inhibitor showed no inhibitory activities toward trypsin and thrombin. However, the inhibitor presented activity toward subtilisin and chymotrypsin. These datas indicate that this molecule is a novel inhibitor to HNE and we named it Vigna unguiculata Elastase Inhibitor (VuEI).
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Books on the topic "Serine protease inhibitor"

1

Festoff, Barry W., and Daniel Hantaï, eds. Serine Proteases and Their Serpin Inhibitors in the Nervous System. Boston, MA: Springer New York, 1990. http://dx.doi.org/10.1007/978-1-4684-8357-4.

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Carthy, Barry Mc. Ovalbumin, gene Y and serpin inhibitory function. Dublin: University College Dublin, 1998.

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West, A. Investigations by mass spectrometry of the interactions of novel serine protease inhibitors with Herpes Simplex Virus type 2 and Human Cytomegalovirus proteases. [s.l.]: typescript, 1999.

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Barnes, Ruth C. Identification and characterisation of a novel human serpin gene: Leupin. Dublin: University College Dublin, 1998.

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Lai, Weidong George. Probing the stereospecificites of serine proteases using chiral aromatic aldehyde inhibitors and exploring the specificities of subtilisin lentus and its serine mutant. Ottawa: National Library of Canada, 1996.

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Georgiev, Bojidor. Serpins and protein kinase inhibitors: Novel functions, structural features and molecular mechanisms. New York: Nova Science Publishers, 2010.

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NATO Advanced Research Workshop on Regulation of Extravascular Fibrinolysis in Nervous System Development and Disease (1989 Maratea, Italy). Serine proteases and their serpin inhibitors in the nervous system: Regulation in development and in degenerative and malignant disease. Edited by Festoff Barry W, Hantaï Daniel, and North Atlantic Treaty Organization. Scientific Affairs Division. New York: Plenum Press, 1990.

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Vacca, Joseph P., Gerd Folkers, Raimund Mannhold, and Hugo Kubinyi. Proteases as Drug Targets: Serine Proteases. Wiley & Sons, Incorporated, John, 2010.

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Festoff, Barry W. Serine Proteases and Their Serpin Inhibitors in the Nervous System. Springer, 1990.

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Poduch, Ewa. Kinetic studies of novel reversible and mechanism-based inhibitors of orotidine monophosphate decarboxylase and serine proteases. 2006.

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Book chapters on the topic "Serine protease inhibitor"

1

Gubernator, K., H. J. Ammann, C. Broger, D. Bur, D. M. Doran, P. R. Gerber, K. Müller, and Th M. Schaumann. "Molecular modelling contributions to serine protease and serine esterase inhibitor design." In Trends in QSAR and Molecular Modelling 92, 52–58. Dordrecht: Springer Netherlands, 1993. http://dx.doi.org/10.1007/978-94-011-1472-1_7.

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Furukawa, Kenei, Tadashi Uwagawa, and Katsuhiko Yanaga. "Anti-Tumor Effect of Synthetic Serine Protease Inhibitor." In Antitumor Potential and other Emerging Medicinal Properties of Natural Compounds, 205–12. Dordrecht: Springer Netherlands, 2013. http://dx.doi.org/10.1007/978-94-007-6214-5_13.

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Salek Maghsoudi, Armin, Shokoufeh Hassani, Kayvan Mirnia, and Mohammad Abdollahi. "Serpin A12 (Vaspin) as a Serine Protease Inhibitor." In Biomarkers in Diabetes, 153–69. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-08014-2_7.

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Salek Maghsoudi, Armin, Shokoufeh Hassani, Kayvan Mirnia, and Mohammad Abdollahi. "Serpin A12 (Vaspin) as a Serine Protease Inhibitor." In Biomarkers in Diabetes, 1–17. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-81303-1_7-1.

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Flecker, Peter. "Analysis of Structure-Activity Relationships of the Bowman-Birk Inhibitor of Serine Proteinases." In Protease Inhibitors as Cancer Chemopreventive Agents, 161–76. Boston, MA: Springer US, 1993. http://dx.doi.org/10.1007/978-1-4615-2882-1_9.

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Nakamura, Takehiro, Yasuhiro Kuroda, Naohisa Hosomi, Naohiko Okabe, Nobuyuki Kawai, Takashi Tamiya, Guohua Xi, Richard F. Keep, and Toshifumi Itano. "Serine Protease Inhibitor Attenuates Intracerebral Hemorrhage-Induced Brain Injury and Edema Formation in Rat." In Brain Edema XIV, 307–10. Vienna: Springer Vienna, 2009. http://dx.doi.org/10.1007/978-3-211-98811-4_57.

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Tanzi, Rudolph E. "A Serine Protease Inhibitor Domain Encoded Within the Alzheimer Disease-Associated Amyloid ß-Protein Precursor Gene." In Serine Proteases and Their Serpin Inhibitors in the Nervous System, 313–19. Boston, MA: Springer New York, 1990. http://dx.doi.org/10.1007/978-1-4684-8357-4_28.

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Simon, Sanford R. "Oxidants, Metalloproteases and Serine Proteases in Inflammation." In Proteases, Protease Inhibitors and Protease-Derived Peptides, 27–37. Basel: Birkhäuser Basel, 1993. http://dx.doi.org/10.1007/978-3-0348-7397-0_3.

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Seto, Shinji, Masazumi Akahoshi, Shigeru Kusano, Shin-ichi Kitamura, and Kunitake Hashiba. "Central Effect of Aprotinin, a Serine Protease Inhibitor, on Blood Pressure in Spontaneously Hypertensive and Wistar-Kyoto Rats." In Advances in Experimental Medicine and Biology, 49–54. Boston, MA: Springer US, 1989. http://dx.doi.org/10.1007/978-1-4615-9546-5_8.

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Urano, Tetsumei, Kiyohito Serizawa, Kenji Sakakibara, Leif Strandberg, Tor Ny, Yumiko Takada, and Akikazu Takada. "The Cleavage of a Serine Protease Inhibitor at the Reactive Center by Its Target Protease: Analysis of the Substrate-Like Form of a Serpin." In Current Aspects of Blood Coagulation, Fibrinolysis, and Platelets, 29–34. Tokyo: Springer Japan, 1993. http://dx.doi.org/10.1007/978-4-431-68323-0_5.

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Conference papers on the topic "Serine protease inhibitor"

1

Tans, G., T. Janssen-Claessen, J. Rosing, and J. H. Griffin. "APPLICATION OF SPECIFIC SERINE PROTEASE INHIBITORS IN ASSAYS FOR ACTIVATED CONTACT FACTORS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643301.

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We developed amidolytic assays to determine human Factor Xlla, Factor XIa and plasma kallikrein in mixtures containing variable amounts of each enzyme. The commercially available chromogenic substrates pro-phe-arg-pNA (S2302 or chromozym PK), glu-pro-arg-pNA (S2366), ile-glu-(piperidyl)-gly-arg-pNA (S2337), and ile-glu-gly-arg-pNA (S2222) were tested for their suitability as substrates in these assays. 8-Factor Xlla, Factor XIa and plasma kallikrein each exhibit considerable activity towards a number of these substrates. This precludes direct quantitation of the individual enzymes when large amounts of other activated contact factors are present. Several serine protease inhibitors were tested on their ability to selectively inhibit those contact factors that may interfere with the factor tested for. Soybean trypsin inhibitor efficiently inhibits kallikrein, inhibits Factor XIa at moderate concentrations, but did not affect the amidolytic activity of Factor Xlla. Therefore, this inhibitor can be used to abolish a kallikrein and Factor XIa contribution in a Factor Xlla assay. We also report the rate constants of inhibition of contact activation factors by three different chloromethylketones. D-phe-pro-arg-CH 2 Cl was moderately active against contact factors (k - 2271 M-ls-1 at pH 8.3) but showed no differences in specif ity. D-phe-phe-arg-CH2 Cl was a very efficient inhibitor of kallikrein (k = 118,000 M-ls-1 at pH 8.3) whereas it slowly inhibited Factor Xlla (k = 1389 M-ls-1) and Factor XIa (k = 110 M-ls-1). Also dansyl-glu-gly-arg-CH2Cl was more reactive towards kallikrein (k 15,662 M-ls-1) than towards Factor Xlla (k = 462 M-ls-1) and Factor XIa (k = 63 M-ls-1). Since phe-phe-arg-CH2Cl is highly specific for kallikrein it can be used in a Factor XIa assay to selectively inhibit kallikrein. Based on the catalytic efficiencies of chromogenic substrate conversion and the inhibition characteristics of serine protease inhibitors and chloromethyl ketones we were able to develop quantitative assays for Factor Xlla, Factor XIa and kallikrein in mixtures of contact activation factors.
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Cheung, A., and K. F. Hebert. "A TUMOR SERINE PROTEASE INHIBITOR WHICH MAY FUNCTION AS A TISSUE PLASMINOGEN ACTIVATOR INHIBITOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644448.

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A protease inhibitor has been isolated from human colorectal adenocarcinomas by extraction with a low ionic strength-buffer and a combination of concanavalin A-Sepharose, Sephadex G-200, DEAE cellulose and chromatofocusing steps. The preparation appeared to be homogeneous upon gel exclusion chromatography and SDS polyacrylamide gel electrophoresis. It had an apparent Mr of ~66,000 and its isoelectric point was 4.6-4.7. The inhibitor was able to bind and inhibit urokinase, plasmin, trypsin, tissue plasminogen activator and thrombin. The bindings appeared to be stoichiometric and relative fast and diisopropylfluorophoshphate interfered with the bindings. However tPA was the only enzyme that was inhibited in a linear concentration-dependent manner.The inhibitor crossreacted with antiserum against al-antitrypsin but not with antisera against β2-macroglobulin, α2-antiplasmin, antithrombin III, or Cl-inhibitor. Whereas αl-antitrypsin completely inhibited the amidolytic activity of elastase, the tumor inhibitor had no effect on elastase under the same conditions.
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Strandberg, L., D. Lawrence, and T. Ny. "ISOLATION OF THE GENOMIC REGION CODING FOR TYPE-1 PLASMINOGEN ACTIVATOR INHIBITOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644439.

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The type-1 Plasminogen Activator Inhibitor (PAI-1) has recently been identified as a member of the Serine Protease Inhibitor family (SERPINS). This family of proteins contain many serine protease inhibitors but also functionally unrelated proteins like ovalbumin and anginotensinogen. PAI-1 inhibits both u-PA and t-PA and might therefore be an important regulator of the fibrinolytic system.In order to study the evolution of the Serpin family as well as PAI-1 gene expression we have isolated the genomic region carrying the PAI-1 gene. A cDNA sequence for PAI-1 was used as probe to screen a human genomic library. When 2 million independent phages were screened, 13 positive clones were isolated. Characterisation of these clones showed that they could be divided into 3 overlapping groups covering a genomic region of approximately 30 kb. The gene was localized and characterized by restriction enzyme analysis, southern blotting using cDNA and oligomer probes, and DNA sequencing.
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Carrell, R. W., P. D. Christey, and D. R. Boswell. "SERPINS: ANTITHROMBIN AND OTHER INHIBITORS OF COAGULATION AND FIBRINOLYSIS. EVIDENCE FROM AMINO ACID SEQUENCES." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642896.

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A number of the key inhibitors of coagulation and fibrinolysis have recently been shown to be members of the same superfamily of serine protease inhibitors, the serpins. The archetypes of the group are alpha-l-antitrypsin and antithrombin and it includes antiplasmin, C1-inhibitor, heparin cofactor II and the newly recognised inhibitors of plasminogen activators and activated Protein C. Alignment of their structures shows that they have the same skeletal three-dimensional conformation and, by inference, the same general function mechanisms.The serpins have a reactive centre, primarily dependent on a single amino acid, exteriorly placed on a stressed peptide loop. This functions by offering the cognate protease a high-affinity substrate that resists complete cleavage to form a tight 1:1 complex of inhibitor and protease that is subsequently removed from the circulation. The loop is vulnerable to cleavage with resulting loss of inhibitory activity. This irreversible switch is utilised: pathologically by venom and invasive bacterial proteases; and physiologically by the neutrophil leucocyte to modify local inflammatory responses. These mechanisms contribute to the changes seen in DIC and the shock syndromes.Modelling of antithrombin indicates the likely topological features involved in the binding of heparin, namely a sphere of positive charge centred on the A and D helices and involving Arg 47, Lys 125, Arg 129 and probably Arg 132 and Lys 133.Because the serpins are largely dependent for their specificityon a single amino acid it is now possible to precisely tailor inhibitory activity by site specific mutation. This has been used to produce recombinant antitrypsins that function as an improved inhibitor of neutrophil proteases (valine or leucine reactive centre), or as an analogue of antithrombin (arginine reactive centre). An elegant application of this approach is the engineered mutants of antiplasmin recently described by Holmes, Collen and colleagues (Leuven).
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5

de Agostini, A., F. Barja, S. Carrel, P. C. Harpel, and M. Schapira. "C1 -INHIBITOR: STRUCTURE-ACTIVITY RELATIONSHIPS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642903.

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Cl-inhibitor [C1 -In] and other protease inhibitors of the serpin superfamily inactivate serine proteases by forming bimolecular enzyme-inhibitor complexes, a reaction that is associated with changes in the inhibitor conformation. To determine the significance of these changes, we have examined the influence of various treatments on the binding to C1-In of monoclonal antibody 4C3. This antibody was previously shown to bind to an epitope created during the reaction of C1-In with the Arg-specific protease plasma kallikrein [K]: the site for 4C3 was expressed on the K-C1-In complex, on C1-In cleaved at position Pi and released from K-C1-In [C1-In*], but not on unreacted C1-In. The binding of 4C3 to the various forms of C1-In was now measured by radioimmunoassay and Western blot. Following inactivation by C1-In of the Arg-specific enzymes factor XII active fragment [Xllf] or C1s, the binding site for 4C3 was detectable on XIIf-CI-In, C1s-C1-In and C1-In*. However, when K or Xllf were incubated with heat-inactivated C1-In, bo+h enzymes remained active, no complex was formed, and the site for 4C3 was not created. When C1-In was cleaved by neutrophil elastase [E] (a Met-orVal-specific protease that is not inhibited by C1 -In), the 1st cleavage product C1-In’ retained inhibitory activity (as shown by its ability to form a complex with Xllf) but did not bind 4C3. However, subsequent cleavage of C1-In’ by E at position P3 yielded C1-In’, a product which was inactive but bound 4C3. Thus, identical conformational changes of C1-In (as assessed by the emergence of the site for 4C3) are seen when Cl-In inactivates its target enzymes while being cleaved at Pi or when the inhibitor is catalytically inactivated by cleavage at P3. Therefore, these changes are necessary but not sufficient for observing enzyme inactivation.
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6

Baker, J. B., M. P. McGrogan, C. Simonsen, R. L. Gronke, and B. W. Festoff. "STRUCTURE AND PROPERTIES OF PROTEASE NEXIN I." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644765.

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Human foreskin fibroblasts secrete several different serine protease inhibitors which differ in size and protease specificities. These proteins, called protease nexins (PNs) all form SDS-resistant complexes with their protease targets. Fibroblast surface receptors recognize the protease-PN complexes and mediate their delivery to lysosomes. PNI is a 45 kilodalton glycoprotein that rapidly inhibits several arg or lys-specific proteases including trypsin, thrombin, and urokinase (k assoc.∼ 4×l06,∼ 6×105 and ∼ 2×105, m−1s−1 respectively). Like antithrombin III, PNI binds heparin and inhibits thrombin at a vastly accelerated rate in the presence of this glycoaminoglycan. Immunofluorescence studies show that in addition to secreting PNI foreskin fibroblasts carry this inhibitor on their surfaces. PNI cDNA has been cloned and sequenced. A mixed oligonucleotide probe derived from PNI N-terminal sequence was used to probe a foreskin fibroblast cDNA library constructed with λGT10. Identification of PNI cDNAs has been verified by sequencing and by expressing active PNI protein in mammalian cells. The full amino acid sequence of PNI, deduced from cDNA sequencing, is 392 residues long and has 30% homology to antithrombin III. An arg-ser pair 32 residues from the C-terminus of the inhibitor is proposed as the reactive center P1-P1 residues. In the hinge region a lys residue is present in a position occupied by a ginor glu residue in other serpins. PNI mRNA exists in 2 slightly different forms:One (αPNI) yields a thr-arg-ser sequence wherethe other βPNI) yields a thr-thr-gly-ser sequence. The presence of the appropriate splice acceptor sites in the genome indicates that these forms are generated from a single gene by alternative splicing. Expressed aPNI and 0PNI proteins both bind thrombin and urokinase. In foreskin fibroblaststhe α form of PNI mRNA predominates over the β form by about 2:1. In foreskin fibroblast cultures secreted PNI inhibits the mitogenic response to thrombin and regulate secreted urokinase. Purified PNI added to human fibrosarcoma (HT1080) cells inhibitsthe tumor cell-mediated destruction of extracellular matrix and transiently, but dramatically, inhibits tumor cell growth. PNI or PNI-like inhibitors may function at multiple physiological sites. The β form of PNI is virtually identical to a glia-derived neurite promoting factor, the cDNA for which has been recently cloned and sequenced by Gloor et al (1). The neurite outgrowth activity of PNI may result from inhibition of a thrombin-like protease that is associated with neurons, since a number of thrombin inhibitors stimulate neurite extension. Recent immunofluoresence experiments, carried out with D. Hantai (Inserm; Paris) demonstrate that anti-PNI antibody intensely stains neuromuscular synapses. In addition, a PNI-like inhibitor is associated with platelets. At low (0.5 nM <) 125I-thrombin concentrations formation of 125I-thrombin-platelet PNI complexes accounts for most of the specific binding of 125I-thrombin to platelets (2). Although the platelet-associated form of PNI is electrophoretically and immunologically indistinguishable from fibroblast PNI, it does not bind urokinase, suggesting that it may be distinct.(1) Gloor, S., K. Odink, J. Guenther, H. Nick, and D. Monard. (1986) Cell 47:687-693.(2) Gronke, R.S., B.L. Bergman, and J.B. Baker. (1987) J. Biol. Chem. (in press)
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Suzuki, Koji, Yoshihiro Deyashiki, Junji Nishioka, Kazunori Toma, and Shuji Yamamoto. "THE INHIBITOR OF ACTIVATED PROTEIN C: STRUCTURE AND FUNCTION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642963.

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In the final step of protein C pathway, activated protein C (APC) is neutralized with a plasma inhibitor, termed protein C inhibitor (PCI). PCI was first described by Marlar and Griffin (1980) and then isolated from human plasma as a homogeneous form and characterized by the authors (1983). PCI is a single chain glycoprotein with M 57,000 and a plasma concentration of 5 ug/ml. Analysis of a cDNA nucleotide sequence has clarified that a precursor of human PCI consists of a mature protein of 387 amino acid residues (M 43,759) and a signal peptide of 19 amino acid residues. Only one cysteine residue is present in the entire protein as in α1antitrypsin (α1AT) and α1antichymotrypsin (α1ACT). Three Asn-X-Ser/Thr sequences and two Ser/Thr-X-X-Pro sequences are present as potential attachment sites of carbohydrate chains. Based on the amino acid sequence of the carboxyl-terminal peptide released from the inhibitor by APC digestion, the reactive site peptide bond of PCI was found to be Arg(354)-Ser(355). It is similar to the reactive sites of the other serine protease inhibitors which are located to their carboxyl-terminal Arg(393)-Ser (394), Met(358)-Ser(359) and Leu(358)-Ser(359) in antithrombin III, α1AT and α1ACT, respectively. The alignment of the amino acid sequence of PCI with heparin cofactor II, α1plasmin inhibitor, ovalbumin, angiotensinogen and the above noted plasma inhibitors showed that PCI is a member of serine protease inhibitor superfamily. PCI inhibits APC noncompetitively in a 1:1 stoichiometry and forms a covalent acyl-bond with a Ser residue in the active center of APC. The half life of APC in plasma approximately 30 min, which is rather slow compared with the other protease inhibitors. However, optimal concentrations of heparin, dextran sulfate and its derivatives potentiate the rate of inhibition 30-60 fold. PCI has Ki of 10-8m for APC, and can inhibit thrombin, Factor Xa, urokinase and tissue plasminogen activator as well in the presence of heparin or dextran sulfate, though the Ki for these enzymes is slightly higher. During the complex formation with APC, PCI is cleaved by the complexed APC to form a modified form with M 54,000. PCI is synthesized in several hepatoma cell lines and decreased in plasma of patients with liver cirrhosis. It is also decreased in patients with DIC or those during cardiopulmonary bypass in parallel with the decrease in protein C, suggesting that PCI participates in regulation of the protein C pathway in intravascular coagulation. Recently, we have obtained the recombinant PCI from COS-1 cells which were transfected with expression vector pSV2 containing the cDNA of PCI. The recombinant PCI had the same Mr and specific activity as the protein purified from plasma. It also had an affinity for heparin and dextran sulfate. Moreover, we have predicted a three dimentional structure of the proteolytically modified PCI with computer graphics based on its amino acid sequence homology with the modified α1AT whose structure had been elucidated with X-ray crystallography. All potential carbohydrate attachment sites were estimated to exist on the surface of the protein. Succesively we have constructed the interaction model between the intact PCI predicted from the modified form and the active center of APC which was simulated from that of trypsin. From the model, it was observed that the amino-group of Arg (354, PI site) of PCI could strongly interact with the carboxy1-group of Asp (88, SI site) of the heavy chain of APC at the base of the active center pocket of the enzyme.
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Bergin, David A., Emer P. Reeves, and Noel G. McElvaney. "Alpha-1 Antitrypsin: A Serine Protease Inhibitor With Novel Anti-TACE Activity." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a2639.

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Caruso, Joseph A., Cansu Karakas, Kelly Hunt, and Khandan Keyomarsi. "Abstract 2466: Elafin, a serine protease inhibitor, is deregulated during breast cancer progression." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2466.

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Gu, Qijuan. "Identification, characterization and functional analysis of a serine protease inhibitor (CvT-serpin) from Cotesia vestalis teratocytes." In 2016 International Congress of Entomology. Entomological Society of America, 2016. http://dx.doi.org/10.1603/ice.2016.112554.

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Reports on the topic "Serine protease inhibitor"

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Sanders, Tanya C. A New Class of Serine and Cysteine Protease Inhibitor with Chemotherapeutic Potential. Fort Belvoir, VA: Defense Technical Information Center, June 1999. http://dx.doi.org/10.21236/ada370850.

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Sanders, Tanya C. A New Class of Serine and Cysteine Protease Inhibitor with Chemotherapeutic Potential. Fort Belvoir, VA: Defense Technical Information Center, July 1998. http://dx.doi.org/10.21236/ada353868.

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Lin, Chen-Yong. An Epithelial-Derived, Integral Membrane, Kunitz-Type Serine Protease Inhibitor in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, August 2005. http://dx.doi.org/10.21236/ada442974.

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Lin, Chen-Yong. An Epithelial-Derived, Integral Membrane, Kunitz-Type Serine Protease Inhibitor in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, August 2002. http://dx.doi.org/10.21236/ada410178.

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Lin, Chen-Yong. An Epithelial-Derived, Integral Membrane, Kunitz-Type serine Protease Inhibitor in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, August 2004. http://dx.doi.org/10.21236/ada435266.

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Lin, Chen-Yong. An Epithelial-Derived Integral Membrane Kunitz-Type Serine Protease Inhibitor in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, August 2003. http://dx.doi.org/10.21236/ada420072.

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Dickson, Robert B. A Novel Serine Protease Target for Prevention of Breast Cancer by a Soy Bean-Derived Inhibitor. Fort Belvoir, VA: Defense Technical Information Center, July 2001. http://dx.doi.org/10.21236/ada396285.

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Johnson, Michael D. Breast Cancer Metastasis and the Balance of the Serine Protease Matriptase and Its Inhibitor KSPI-1. Fort Belvoir, VA: Defense Technical Information Center, July 2001. http://dx.doi.org/10.21236/ada400456.

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Dickson, Robert. A Novel Serine Protease Target for Prevention of Breast Cancer by a Soy Bean-Derived Inhibitor. Fort Belvoir, VA: Defense Technical Information Center, July 2000. http://dx.doi.org/10.21236/ada383190.

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Manulis, Shulamit, Christine D. Smart, Isaac Barash, Guido Sessa, and Harvey C. Hoch. Molecular Interactions of Clavibacter michiganensis subsp. michiganensis with Tomato. United States Department of Agriculture, January 2011. http://dx.doi.org/10.32747/2011.7697113.bard.

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Abstract:
Clavibacter michiganensis subsp. michiganensis (Cmm), the causal agent of bacterial wilt and canker of tomato, is the most destructive bacterial disease of tomato causing substantial economic losses in Israel, the U.S.A. and worldwide. The molecular strategies that allow Cmm, a Gram-positive bacterium, to develop a successful infection in tomato plants are largely unknown. The goal of the project was to elucidate the molecular interactions between Cmmand tomato. The first objective was to analyze gene expression profiles of susceptible tomato plants infected with pathogenic and endophytic Cmmstrains. Microarray analysis identified 122 genes that were differentially expressed during early stages of infection. Cmm activated typical basal defense responses in the host including induction of defense-related genes, production of scavenging of free oxygen radicals, enhanced protein turnover and hormone synthesis. Proteomic investigation of the Cmm-tomato interaction was performed with Multi-Dimensional Protein Identification Technology (MudPIT) and mass spectroscopy. A wide range of enzymes secreted by Cmm382, including cell-wall degrading enzymes and a large group of serine proteases from different families were identified in the xylem sap of infected tomato. Based on proteomic results, the expression pattern of selected bacterial virulence genes and plant defense genes were examined by qRT-PCR. Expression of the plasmid-borne cellulase (celA), serine protease (pat-1) and serine proteases residing on the chp/tomA pathogenicity island (chpCandppaA), were significantly induced within 96 hr after inoculation. Transcription of chromosomal genes involved in cell wall degradation (i.e., pelA1, celB, xysA and xysB) was also induced in early infection stages. The second objective was to identify by VIGS technology host genes affecting Cmm multiplication and appearance of disease symptoms in plant. VIGS screening showed that out of 160 tomato genes, which could be involved in defense-related signaling, suppression of 14 genes led to increase host susceptibility. Noteworthy are the genes Snakin-2 (inhibitor of Cmm growth) and extensin-like protein (ELP) involved in cell wall fortification. To further test the significance of Snakin -2 and ELP in resistance towards Cmm, transgenic tomato plants over-expressing the two genes were generated. These plants showed partial resistance to Cmm resulting in a significant delay of the wilt symptoms and reduction in size of canker lesion compared to control. Furthermore, colonization of the transgenic plants was significantly lower. The third objective was to assess the involvement of ethylene (ET), jasmonate (JA) and salicylic acid (SA) in Cmm infection. Microarray and proteomic studies showed the induction of enzymes involved in ET and JA biosynthesis. Cmm promoted ET production 8 days after inoculation and SIACO, a key enzyme of ET biosynthesis, was upregulated. Inoculation of the tomato mutants Never ripe (Nr) impaired in ET perception and transgenic plants with reduced ET synthesis significantly delayed wilt symptoms as compared to the wild-type plants. The retarded wilting in Nr plants was shown to be a specific effect of ET insensitivity and was not due to altered expression of defense related genes, reduced bacterial population or decrease in ethylene biosynthesis . In contrast, infection of various tomato mutants impaired in JA biosynthesis (e.g., def1, acx1) and JA insensitive mutant (jai1) yielded unequivocal results. The fourth objective was to determine the role of cell wall degrading enzymes produced by Cmm in xylem colonization and symptoms development. A significance increase (2 to 7 fold) in expression of cellulases (CelA, CelB), pectate lyases (PelA1, PelA2), polygalacturonase and xylanases (XylA, XylB) was detected by qRT-PCR and by proteomic analysis of the xylem sap. However, with the exception of CelA, whose inactivation led to reduced wilt symptoms, inactivation of any of the other cell wall degrading enzymes did not lead to reduced virulence. Results achieved emphasized the complexity involved in Cmm-tomato interactions. Nevertheless they provide the basis for additional research which will unravel the mechanism of Cmm pathogenicity and formulating disease control measures.
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