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Literatura académica sobre el tema "Irreversible inhibitor"

Autor: Grafiati

Publicado: 25 de mayo de 2024

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Artículos de revistas sobre el tema "Irreversible inhibitor"

Buneeva, O. A., L. N. Aksenova y A. E. Medvedev. "A Simple Approach for Pilot Analysis of Time-dependent Enzyme Inhibition: Discrimination Between Mechanism-based Inactivation and Tight Binding Inhibitor Behavior". Biomedical Chemistry: Research and Methods 3, n.º 1 (2020): e00115. http://dx.doi.org/10.18097/bmcrm00115.

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The increase in enzyme inhibition developed during prolonged incubation of an enzyme preparation with a chemical substance may be associated with both the non-covalent and also with covalent enzyme-inhibitor complex formation. The latter case involves catalytic conversion of a mechanism-based irreversible inhibitor (a poor substrate) into a reactive species forming covalent adduct(s) with the enzyme and thus irreversibly inactivating the enzyme molecule. Using a simple approach, based on comparison of enzyme inhibition after preincubation with a potential inhibitor at 4ºC or 37ºC we have analyzed inhibition of monoamine oxidase A (MAO A) by known MAO inhibitors pargyline and pirlindole (pyrazidol). MAO A inhibitory activity of pirlindole (reversible tight binding inhibitor of MAO A) assayed after mitochondrial wash was basically the same for the incubation at both 4ºC and 37ºC. In contrast to pirlindole, the effect of pargyline (mechanism based irreversible MAO inhibitor) strongly depended on the temperature of the incubation medium. At 37ºC the residual activity MAO A in the mitochondrial fraction after washing was significantly lower than in the mitochondrial samples incubated with pargyline at 4ºC. Results of this study suggest that using analysis of both time- and temperature-dependence of inhibition it is possible to discriminate mechanism-based irreversible inhibition and reversible tight binding inhibition of target enzym

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Gledhill, L., P. Williams y B. W. Bycroft. "Irreversible inactivation of β-lactamase I from Bacillus cereus by chlorinated 6-spiroepoxypenicillins". Biochemical Journal 276, n.º 3 (15 de junio de 1991): 801–7. http://dx.doi.org/10.1042/bj2760801.

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On incubation of the chlorinated 6-spiroepoxypenicillin anilides (I) and (II) [formula: see text] with beta-lactamase 1 from Bacillus cereus, three distinct processes are observed. The inhibitors act as (a) substrates, the turnover of which respectively results in a single product, namely 6-substituted 2(H)-3,4-dihydro-1,4-thiazine, (b) a transiently inhibited enzyme complex, and finally (c) an irreversibly inactivated enzyme complex. Although differing only in their stereochemistry at one centre, the anilide (K) is a more potent irreversible inactivator of beta-lactamase I than is compound (II). Analysis of irreversibly inactivated beta-lactamase I by isoelectric focusing and inspection of peptide fragmentation maps indicated that irreversible inactivation appears to be accompanied by covalent modification. These studies reveal that the chlorinated 6-spiroepoxypenicillin anilide (I) is a mechanism-based beta-lactamase inhibitor.

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Rožman, Kaja, Evan M. Alexander, Eva Ogorevc, Krištof Bozovičar, Izidor Sosič, Courtney C. Aldrich y Stanislav Gobec. "Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome". Molecules 25, n.º 6 (12 de marzo de 2020): 1305. http://dx.doi.org/10.3390/molecules25061305.

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Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8, 11, 13 and 15, exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N-(cyanomethyl)acetamide 8 (Ki = 5.6 µM) and carboxaldehyde-based derivative 15 (Ki = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with Ki values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957, is a noncompetitive irreversible inhibitor of the mycobacterial proteasome (Ki = 5.2 ± 1.9 µM, kinact/Ki = 96 ± 41 M−1·s−1). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.

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Morgan, Hugh P., Martin J. Walsh, Elizabeth A. Blackburn, Martin A. Wear, Matthew B. Boxer, Min Shen, Henrike Veith et al. "A new family of covalent inhibitors block nucleotide binding to the active site of pyruvate kinase". Biochemical Journal 448, n.º 1 (18 de octubre de 2012): 67–72. http://dx.doi.org/10.1042/bj20121014.

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PYK (pyruvate kinase) plays a central role in the metabolism of many organisms and cell types, but the elucidation of the details of its function in a systems biology context has been hampered by the lack of specific high-affinity small-molecule inhibitors. High-throughput screening has been used to identify a family of saccharin derivatives which inhibit LmPYK (Leishmania mexicana PYK) activity in a time- (and dose-) dependent manner, a characteristic of irreversible inhibition. The crystal structure of DBS {4-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfanyl]benzoic acid} complexed with LmPYK shows that the saccharin moiety reacts with an active-site lysine residue (Lys335), forming a covalent bond and sterically hindering the binding of ADP/ATP. Mutation of the lysine residue to an arginine residue eliminated the effect of the inhibitor molecule, providing confirmation of the proposed inhibitor mechanism. This lysine residue is conserved in the active sites of the four human PYK isoenzymes, which were also found to be irreversibly inhibited by DBS. X-ray structures of PYK isoforms show structural differences at the DBS-binding pocket, and this covalent inhibitor of PYK provides a chemical scaffold for the design of new families of potentially isoform-specific irreversible inhibitors.

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Verdugo, Anael, P. K. Vinod, John J. Tyson y Bela Novak. "Molecular mechanisms creating bistable switches at cell cycle transitions". Open Biology 3, n.º 3 (marzo de 2013): 120179. http://dx.doi.org/10.1098/rsob.120179.

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Progression through the eukaryotic cell cycle is characterized by specific transitions, where cells move irreversibly from stage i −1 of the cycle into stage i . These irreversible cell cycle transitions are regulated by underlying bistable switches, which share some common features. An inhibitory protein stalls progression, and an activatory protein promotes progression. The inhibitor and activator are locked in a double-negative feedback loop, creating a one-way toggle switch that guarantees an irreversible commitment to move forward through the cell cycle, and it opposes regression from stage i to stage i −1. In many cases, the activator is an enzyme that modifies the inhibitor in multiple steps, whereas the hypo-modified inhibitor binds strongly to the activator and resists its enzymatic activity. These interactions are the basis of a reaction motif that provides a simple and generic account of many characteristic properties of cell cycle transitions. To demonstrate this assertion, we apply the motif in detail to the G1/S transition in budding yeast and to the mitotic checkpoint in mammalian cells. Variations of the motif might support irreversible cellular decision-making in other contexts.

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Viczjan, Gabor, Tamas Erdei, Ignac Ovari, Nora Lampe, Reka Szekeres, Mariann Bombicz, Barbara Takacs et al. "A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far". International Journal of Molecular Sciences 22, n.º 18 (11 de septiembre de 2021): 9831. http://dx.doi.org/10.3390/ijms22189831.

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In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A1 adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A1 adenosine receptor agonists (determined using concentration/effect (E/c) curves) if NBTI, a nucleoside transport inhibitor, was present. Based on mathematical modeling, we hypothesized that FSCPX blunted the cardiac interstitial adenosine accumulation in response to nucleoside transport blockade, probably by inhibiting CD39 and/or CD73, which are the two main enzymes of the interstitial adenosine production in the heart. The goal of the present study was to test this hypothesis. In vitro CD39 and CD73 inhibitor assays were carried out; furthermore, E/c curves were constructed in isolated, paced rat and guinea pig left atria using adenosine, CHA and CPA (two A1 adenosine receptor agonists), FSCPX, NBTI and NBMPR (two nucleoside transport inhibitors), and PSB-12379 (a CD73 inhibitor), measuring the contractile force. We found that FSCPX did not show any inhibitory effect during the in vitro enzyme assays. However, we successfully reproduced the paradox effect of FSCPX in the rat model, mimicked the “paradox” effect of FSCPX with PSB-12379, and demonstrated the lipophilia of FSCPX, which could explain the negative outcome of inhibitor assays with CD39 and CD73 dissolved in a water-based solution. Taken together, these three pieces of indirect evidence are strong enough to indicate that FSCPX possesses an additional action besides the A1 adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.

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Kondža, Martin, Mirza Bojić, Ivona Tomić, Željan Maleš, Valentina Rezić y Ivan Ćavar. "Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids". Molecules 26, n.º 10 (19 de mayo de 2021): 3018. http://dx.doi.org/10.3390/molecules26103018.

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Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: IC50 = 2.5 ± 0.6 µM, Ki = 2.4 ± 1.0 µM, kinact = 0.07 ± 0.01 min−1, kinact/Ki = 0.03 min−1 µM−1. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food–drug interactions have to be assessed clinically.

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Espín, J. C. y J. Tudela. "Experimental approach to the kinetic study of unstable site-directed irreversible inhibitors: kinetic origin of the apparent positive co-operativity arising from inactivation of trypsin by p-amidinophenylmethanesulphonyl fluoride". Biochemical Journal 299, n.º 1 (1 de abril de 1994): 29–35. http://dx.doi.org/10.1042/bj2990029.

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Experimental characterization of enzyme inactivation by unstable irreversible inhibitors has only previously been carried out by using discontinuous methods involving preincubation, removal of samples and further residual activity assays. A continuous method for the kinetic study of these inhibitors in the presence of an auxiliary substrate was recently proposed in a theoretical study. This method was based on approximate expressions for the evolution of the product concentration, which contained series expansions with five or more exponential terms, seriously complicating their use in practice. In the present paper, a new experimental method has been developed for the kinetic study of unstable and site-directed irreversible inhibitors, considering two different ranges of inhibitor concentration. Thus at low inhibitor concentrations, the system evolves from an initial to a final steady state, the rates of which are described by exact analytical equations. At high inhibitor concentrations, however, the product accumulation can be described by an exact uniexponential equation. This simple and efficient method has been applied to the kinetic study of trypsin inactivation by p-amidinophenylmethanesulphonyl fluoride, near the optimum pH of the enzyme. The dependence of the final steady-state rate on the substrate concentration shows apparent positive co-operativity which has not previously been reported. The kinetic origin of this type of co-operativity is predicted by one of the exact analytical equations derived here. The instability of new protein and non-protein irreversible inhibitors has to be carefully characterized to prevent true unstable irreversible inhibitors being wrongly described as allosteric reversible inhibitors.

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Bitonti, A. J., P. J. Casara, P. P. McCann y P. Bey. "Catalytic irreversible inhibition of bacterial and plant arginine decarboxylase activities by novel substrate and product analogues". Biochemical Journal 242, n.º 1 (15 de febrero de 1987): 69–74. http://dx.doi.org/10.1042/bj2420069.

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Arginine decarboxylase (ADC) activity from Escherichia coli and two plant species (oats and barley) was inhibited by five new substrate (arginine) and product (agmatine) analogues. The five compounds, (E)-alpha-monofluoromethyldehydroarginine (delta-MFMA), alpha-monofluoromethylarginine (MFMA), alpha-monofluoromethylagatine (FMA), alpha-ethynylagmatine (EA) and alpha-allenylagmatine (AA), were all more potent inhibitors of ADC activity than was alpha-difluoromethylarginine (DFMA), the only irreversible inhibitor of this enzyme described previously. The inhibition caused by the five compounds was apparently enzyme-activated and irreversible, since the loss of enzyme activity followed pseudo-first-order kinetics, was time-dependent, the natural substrate of ADC (arginine) blocked the effects of the inhibitors, and the inhibition remained after chromatography of inhibited ADC on Sephadex G-25 or on overnight dialysis of the enzyme. DFMA, FMA, delta-MFMA and MFMA were effective at very low concentrations (10 nM-10 microM) at inhibiting ADC activity in growing E. coli. FMA was also shown to deplete putrescine effectively in E. coli, particularly when combined with an inhibitor of ornithine decarboxylase, alpha-monofluoromethyl-putrescine. The potential uses of the compounds for the study of the role of polyamine biosynthesis in bacteria and plants is discussed.

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Liyanage, Piyumi Dinusha, Pabudi Weerathunge, Mandeep Singh, Vipul Bansal y Rajesh Ramanathan. "L-Cysteine as an Irreversible Inhibitor of the Peroxidase-Mimic Catalytic Activity of 2-Dimensional Ni-Based Nanozymes". Nanomaterials 11, n.º 5 (13 de mayo de 2021): 1285. http://dx.doi.org/10.3390/nano11051285.

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The ability to modulate the catalytic activity of inorganic nanozymes is of high interest. In particular, understanding the interactions of inhibitor molecules with nanozymes can bring them one step closer to the natural enzymes and has thus started to attract intense interest. To date, a few reversible inhibitors of the nanozyme activity have been reported. However, there are no reports of irreversible inhibitor molecules that can permanently inhibit the activity of nanozymes. In the current work, we show the ability of L-cysteine to act as an irreversible inhibitor to permanently block the nanozyme activity of 2-dimensional (2D) NiO nanosheets. Determination of the steady state kinetic parameters allowed us to obtain mechanistic insights into the catalytic inhibition process. Further, based on the irreversible catalytic inhibition capability of L-cysteine, we demonstrate a highly specific sensor for the detection of this biologically important molecule.

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Tesis sobre el tema "Irreversible inhibitor"

Büchold, Christian. "Synthese und Testung cis-konfigurierter Aziridine als pseudo-irreversible Inhibitoren der sekretorischen Aspartatproteasen von Candida albicans". kostenfrei, 2009. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2009/3935/.

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Smar, Michael William. "Part 1: Reversible and irreversible inhibitors of aldose reductase as probes of the inhibitor binding site. Part 2: Synthesis of permanently charged and permanently uncharged dopamine agonists /". The Ohio State University, 1988. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487597424138323.

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Borrello, Maria Teresa. "Reversible and irreversible LSD1 inhibitors". Thesis, University of East Anglia, 2016. https://ueaeprints.uea.ac.uk/59682/.

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Environmental factors and lifestyle can alter the way our genes are expressed influencing a network of chemical switches within our cells collectively known as the Epigenome. Among the epigenetic mechanisms orchestrating the gene expression, methylation is of foremost importance and probably fair to say, still incompletely decoded. Dysregulations of histone methylation patterns lead to the repression or activation of signalling pathways that often promote the genesis and progression of disease states. Lysine specific demethylase 1 (LSD1) oxidatively removes methyl groups from histone H3 and its aberrant activity has been correlated with the development of a broad range of pathologies. Therefore, specific inhibitors of LSD1 have potential in pharmacological applications. Research into LSD1 and its functions in normal and abnormal cells has been hindered by the lack of a specific and potent suppressor. The development of a selective inhibitor could not only foster the understanding of the biological roles of LSD1 but also represent a breakthrough for the design of novel drugs for a range of burdensome diseases. Here we investigate on reversible and irreversible inhibitors of LSD1, with the hope of broadening the current knowledge on this epigenetic target. By analysing the LSD1 interaction with the transcription factor Snail-1, we generated a series of small peptides as potential reversible inhibitors. The synthetic peptides were then evaluated in cellular assays. In search of novel non-covalent LSD1 blockers, we next explored Phage Display technology. Thereafter, we targeted LSD1 covalently by synthesising multiple structural analogues of the clinically used antidepressant TCP (Parnate®), which is a known irreversible suppressor of LSD1 activity. We evaluated their ability of inhibiting LSD1 in a cell-free assay and the compounds showing enzymatic inhibition were tested as potential anti-proliferative and differentiating agents in leukaemia cell lines. Finally, we generated activity-based probes to fluorescently label LSD1 for biological applications.

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Burger, Alain. "Inhibiteurs irreversibles de la biosynthese de l'ecdysone". Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13081.

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Coxon, Christopher Robert. "Design and synthesis of irreversible inhibitors of Nek2 kinase". Thesis, University of Newcastle Upon Tyne, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627743.

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Snider, Catherine E. "Synthesis and biochemical evaluation of irreversible inhibitors of aromatase /". The Ohio State University, 1986. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487266362338344.

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Berabez, Rayan. "Conception et validation préclinique de nouveaux inhibiteurs de LIMK pour le traitement de la Neurofibromatose de type 1". Electronic Thesis or Diss., Orléans, 2023. http://www.theses.fr/2023ORLE1070.

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La neurofibromatose de type 1 (NF1) est une maladie génétique qui se manifeste entre autre par l'apparition de tumeurs bénignes localisées au niveaux des terminaux nerveux appelés neurofibromes cutanés (NFc). Au cours de ces dernières années, de nouvelles cibles thérapeutiques sont apparues telles que les LIM kinases (LIMKs), enzymes responsables du dynamisme du cytosquelette et dont la suractivation est liée à différentes pathologies comme la NF1, le glioblastome ou l'ostéosarcome. Un travail de chimie médicinale a été donc initié dans le but de concevoir de nouveaux inhibiteurs sélectifs des LIMKs. Dans un premier temps, des études de relations structure-activité (RSA) ont été réalisées sur les 3 principaux sites de pharmacomodulations du composé de type pyrrolopyrimidine préalablement développé par notre équipe. Le développement de différentes stratégies de synthèse a été entrepris permettant un accès efficace à un grand nombre de produits finaux (84). L'optimisation de la partie aniline des composés a mené à la synthèse de 49 inhibiteurs des LIMKs, avec des constantes d'inhibition inférieures à 5 nM pour certains d'entre eux. Par la suite, l'élaboration d'une voie de synthèse optimisée en 15 étapes a permis de remplacer le cycle central 3,6-dihydropyridine jusqu'alors inchangé, par un dérivé de l'acide 1-aminocyclohex-3-ène-1-carboxylique. Enfin, une nouvelle série d'inhibiteurs a été préparée en remplaçant la base hétérocyclique pyrrolo[2,3-d]pyrimidine par des dérivés 7-azaindoliques. Nous avons observé une meilleure sélectivité pour les LIMKs vis-à-vis des ROCKs pour les 23 produits obtenus. Des évaluations in vitro approfondies de nos meilleurs inhibiteurs sur plusieurs lignées cellulaires ont mené à la sélection de deux composés pour être utilisés lors d'essais in vivo sur un modèle de souris original de NF1. En parallèle, de nouveaux modes d'inhibition des LIMKs ont été développés avec la synthèse d'un inhibiteur irréversible ciblant LIMK1, ainsi que 4 PROTACs qui ont provoqué la dégradation des LIMKs par la voie protéasome-ubiquitine sur plusieurs lignées cellulaires
Neurofibromatosis type 1 (NF1) is a genetic disease characterized by the development of cutaneous neurofibromas (cNF) (benign tumors) located at nerve endings. LIM kinases (LIMKs), enzymes responsible for cytoskeleton dynamics, have emerged in recent years as valid therapeutic targets for this disease. These enzymes are overactivated in several pathologies including NF1, glioblastoma or osteosarcoma. A medicinal chemistry project was therefore initiated with the aim of designing new selective inhibitors of LIMKs. Initially, structure-activity relationship (SAR) studies were conducted on the 3 main pharmacomodulation sites of the pyrrolopyrimidine-type compounds previously developed by our team. The development of various synthetic strategies was undertaken, allowing efficient access to a large number of final products (84). Optimization of the aniline portion of the compounds led to the synthesis of 49 LIMKs inhibitors, with inhibition constants lower than 5 nM for several derivatives. Subsequently, an optimized 15 steps synthetic route was developed to replace the previously unchanged central ring 3,6-dihydropyridine with a derivative of 1-aminocyclohex-3-ene-1-carboxylic acid. Finally, a new series of inhibitors was developed by replacing the heterocyclic pyrrolo[2,3-d]pyrimidine base by 7-azaindole derivatives. Improved LIMK vs. ROCK selectivity was observed among the 23 obtained products. Following extensive in vitro evaluation of our best inhibitors on several cell lines, two compounds were selected for in vivo trials on an original mouse model of NF1. In parallel, new modes of LIMKs inhibition were developed with the synthesis of an irreversible inhibitor targeting LIMK1, as well as 4 PROTACs that induced LIMKs degradation through the ubiquitin-proteasome system in several cell lines

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Äbelö, Angela. "Pharmacodynamic Modelling of Irreversible and Reversible Gastric Proton Pump Inhibitors". Doctoral thesis, Uppsala University, Division of Pharmacokinetics and Drug Therapy, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3778.

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Acid related diseases like GERD, duodenal-and gastric ulcers and H. Pylori-positive peptic ulcer disease are primarily managed by reducing gastric acidity. Irreversible proton pump inhibitors (PPIs) inhibit gastric acid secretion effectively throughout the day by irreversibly inhibiting the gastric proton pump, H+, K+-ATPase, in the parietal cells. Reversible gastric proton pump inhibitors are under development, but have not yet reached clinical use.

The pharmacokinetic/pharmacodynamic (PK/PD) relationships of these compounds are nonlinear, with a delay in the effect-time profile compared to the plasma concentration-time course. PK/PD-modelling was used to characterize and quantify the pharmacological effect with regard to onset, intensity and duration of effect. Models based on functional data, that discriminate between drug-and system-specific parameters, were developed.

In general, the plasma concentration-time course for each individual was approximated by linear interpolation between time-points and served as input into the pharmacodynamic models. A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog described the data well. The model was challenged and found to be robust under different experimental conditions. This model could predict the effect following different exposure of omeprazole and following different histamine provocation. Different fitting approaches (naïve pooling, standard two-stage and nonlinear mixed effects modelling) were compared and resulted in similar parameter estimates. For the reversible inhibitors, a kinetic binding model was finally selected. With a binding model the delay in the effect-time profile is explained by prolonged binding to the enzyme.

Use of these results in drug development can be helpful with regard to selection of drugs for further development and to predict the first clinical dose.

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Ekici, Ozlem Dogan. "Design, synthesis, and evaluation of novel irreversible inhibitors for caspases". Diss., Georgia Institute of Technology, 2003. http://hdl.handle.net/1853/5333.

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Äbelö, Angela. "Pharmacodynamic modelling of irreversible and reversible gastric proton pump inhibitors /". Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3778.

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Libros sobre el tema "Irreversible inhibitor"

Isaacs, Stuart Neal. Premeditated enzyme inactivation: The development of mechanism-based irreversible inhibitors of glyoxalase I as potential anti-cancer agents. [New Haven: s.n.], 1985.

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S, Gray Nathanael, Janne Pasi A y Saghatelian Alan, eds. Targeting `Undruggable' Cancer Proteins with Irreversible Small Molecule Inhibitors: Her3 and KRas. 2014.

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Lambert, David G. Mechanisms and determinants of anaesthetic drug action. Editado por Michel M. R. F. Struys. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199642045.003.0013.

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This chapter is broken into two main sections: a general description of the principles of ligand receptor interaction and a discussion of the main groups of ‘targets’; and explanation of some common pharmacological interactions in anaesthesia, critical care, and pain management. Agonists bind to and activate receptors while antagonists bind to receptors and block the effects of agonists. Antagonists can be competitive (most common) or non-competitive/irreversible. The main classes of drug target are enzymes, carriers, ion channels, and receptors with examples of anaesthetic relevance interacting with all classes. There are many examples in anaesthesia where multiple interacting drugs are co-administered—polypharmacology. To give an example: neuromuscular blockade. Rocuronium is a non-depolarizing neuromuscular blocker acting as a competitive antagonist at the nicotinic acetylcholine receptor. Rocuronium competes with endogenous acetylcholine to shift the concentration–response curve for contraction to the right. The degree of contractility is less for a given concentration of acetylcholine (agonist) in the presence of rocuronium. Using the same principle, the rightward shift can be compensated by increasing the amount of acetylcholine (as long as the amount of rocuronium presented to the receptor as an antagonist remains unchanged, its action can be overcome by increased agonist). Acetylcholine at the effect site is increased by acetylcholinesterase inhibition with neostigmine. One of the side-effects of neostigmine is that it acts as an indirect parasympathomimetic. In the cardiovascular system this would lead to muscarinic receptor-mediated bradycardia; these effects are routinely reversed by the competitive muscarinic antagonist glycopyrrolate.

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Capítulos de libros sobre el tema "Irreversible inhibitor"

Reed, Jessica E. y Jeff B. Smaill. "The Discovery of Dacomitinib, a Potent Irreversible EGFR Inhibitor". En Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage Process Development Volume 1, 207–33. Washington, DC: American Chemical Society, 2016. http://dx.doi.org/10.1021/bk-2016-1239.ch008.

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Verma, Ajit K. "Inhibition of Tumor Promotion by DL-α-Difluoromethylornithine, A Specific Irreversible Inhibitor of Ornithine Decarboxylase". En Antimutagenesis and Anticarcinogenesis Mechanisms II, 195–204. Boston, MA: Springer US, 1990. http://dx.doi.org/10.1007/978-1-4615-9561-8_16.

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Keillor, Jeffrey W., Nicolas Chabot, Isabelle Roy, Amina Mulani, Olivier Leogane y Christophe Pardin. "Irreversible Inhibitors of Tissue Transglutaminase". En Advances in Enzymology - and Related Areas of Molecular Biology, 415–47. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2011. http://dx.doi.org/10.1002/9781118105771.ch10.

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Eremenko, Arkadiy, Il'ya Kurochkin y Nataliya Nechaeva. "Bioanalytical systems based on cholinesterases for detection of organophosphates". En ORGANOPHOSPHORUS NEUROTOXINS, 205–18. ru: Publishing Center RIOR, 2020. http://dx.doi.org/10.29039/32_205-218.

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Various types of electrochemical sensors based on the inhibition of butyrylcholinesterase (BChE) have been presented for the analysis of organophosphates (OPC). A special design of thick film sensors and electrochemical detector for cholinesterases assay and their inhibitors in aqueous samples has been developed. For this assay, thiol sensitive sensors based on screen printed graphite electrode modified with nanoparticles of manganese dioxide were used. High sensitivity of manganese dioxide modified thick film sensors towards thiocholine and therefore low detection limit of BChE (1 pM) enabled their use for subnanomolar detection of an organophosphate pesticide diazinon, and other irreversible inhibitors of BChE. This work also presents modern innovative approach for the analysis of BChE by Raman spectroscopy. New SERS-substrates based on silver paste for sensitive quantification of BChE activity were obtained, characterized and applied to thiocholine detection, with LOD (TCh) being 260 nM. Real samples of human plasma were analyzed; a good correlation between spectrophotometric detection and Raman detection was shown. The developed technique is inexpensive and easy-to-use and has promising potential for analysis of OPC.

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Eremenko, Arkadiy, Il'ya Kurochkin y Nataliya Nechaeva. "Bioanalytical systems based on cholinesterases for detection of organophosphates". En Organophosphorous Neurotoxins, 0. ru: Publishing Center RIOR, 2020. http://dx.doi.org/10.29039/chapter_5e4132b6096d14.18045940.

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Mohutsky, Michael y Stephen D. Hall. "Irreversible Enzyme Inhibition Kinetics and Drug–Drug Interactions". En Methods in Molecular Biology, 57–91. Totowa, NJ: Humana Press, 2014. http://dx.doi.org/10.1007/978-1-62703-758-7_5.

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Mohutsky, Michael y Stephen D. Hall. "Irreversible Enzyme Inhibition Kinetics and Drug–Drug Interactions". En Methods in Molecular Biology, 51–88. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1554-6_3.

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Waring, Michael J. "The Discovery of Osimertinib (TAGRISSO™): An Irreversible Inhibitor of Activating and T790M Resistant Forms of the Epidermal Growth Factor Receptor Tyrosine Kinase for the Treatment of Non-Small Cell Lung Cancer". En Successful Drug Discovery, 341–57. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2018. http://dx.doi.org/10.1002/9783527808694.ch12.

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van Ommen, Ben, Jan J. P. Bogaards, Jan Peter Ploemen, J. van der Greef y Peter J. van Bladeren. "Quinones and their Glutathione Conjugates as Irreversible Inhibitors of Glutathione S-Transferases". En Advances in Experimental Medicine and Biology, 403–6. Boston, MA: Springer New York, 1991. http://dx.doi.org/10.1007/978-1-4684-5877-0_54.

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Moore, Michael L., Stephen A. Fakhoury, William M. Bryan, Heidemarie G. Bryan, Thaddeus A. Tomaszek, Stephan K. Grant, Thomas D. Meek y William F. Huffman. "Peptidyl epoxides as potent, active site-directed irreversible inhibitors of HIV-1 protease". En Peptides, 781–82. Dordrecht: Springer Netherlands, 1992. http://dx.doi.org/10.1007/978-94-011-2264-1_315.

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Actas de conferencias sobre el tema "Irreversible inhibitor"

Visser, A. y D. G. Meuleman. "IRREVERSIBLE INHIBITION OF THE THROMBIN-MEDIATED SIGNAL TRANSFER". En XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644808.

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The inhibition of the thrombin-mediated signal transfer by a common irreversible inhibitor Z of the factor Xa complex (Xc a) and thrombin has been analysed for the two-step process of the Xc a-triggered formation of thrombin andthe consecutive splitting ok a thrombin-specific substrate S. Assuming that both proteolytic processes follow simple Michaelis—Menten kinetics, that the inhibition reactions are second-order and that the prothrombin and irreversible inhibitor are in excess it can be shown that:1. clotting time (tc) is inversely proportional to the time-averaged thrombin concentration2. the endpoint of the conversion of the thrombin specific substrate S reached at exhaustion of thrombin and the Xc a is inversely proportional to the square of the inhibitor concentration3. the continously monitored thrombin generation inhibition is a more sensitive assay than the classical two-stage thrombin generation inhibition assay4. the shift in the effective concentration range of the continuously monitored thrombin generation inhibition assay relative to the continuously monitored anti-Xa assay and to that of the continuously monitored anti-IIa assay, depends on the initial rate of formation of thrombin with the thrombin generation inhibition assay and the original enzyme concentrations of the anti-enzyme assays.It can further be shown that the above conclusions still hold when the Z-mediated (with Z = anti thrombin III e.g.) inhibitions are potentiated by heparin(oid)s.

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Iwamoto, M., N. Sugiyama, T. Sasaki y Y. Abiko. "DOMAIN OF BINDING ACTIVITY WITH PLASMIN KRINGLE IN SYNTHESIZED C-TERMINAL PEPTIDES , OF α2-PLASMIN INHIBITOR". En XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644612.

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The inhibitory reaction between plasmin and α2-plasmin inhibitor (α2-PI) proceeds with two steps, a very fast reversible reaction followed by a slower irreversible transition. The first step is dependent on the interaction between lysine binding site (LBS) of plasmin and the corresponding complementary site of α2-PI (kringle binding site(KBS)). It has been reported that KBS is located in a C-terminal tryptic fragment (T-11; J. Biochem. 99, 1699 (1986)).In order to investigate which amino acid residues of T-ll play important roles in binding of plasmin kringle, we tested inhibitory activity of synthesized peptides on the apparent rate constant in the reaction between α2-PI and plasmin. 50% inhibition concentrations of T-ll, peptide I, II, III and IV were 7, 18, 13, 35 and 250pM respectively, indicating that Leu9-Lysl0 is an important part for binding of T-ll to LBS. Peptide III lost its activity by depletion or amidation of the C-terminal lysine residue.In the system consisted of α2-PI and miniplasmin which lacked kringle 1-4, peptide I did not inhibit the interaction between them. Furthermore, peptide II competitively inhibited the binding of tranexamic acid to kringle 1-3 (Ki 0.85μM).These findings suggest that the C-terminal part is involved in the high affinity binding of α2-PI to plasmin kringle and that LyslO in T-ll and C-terminal carboxyl residue play crucial roles in binding to LBS of kringle.

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Qiao, Lixin, Mariana Nacht, Michael P. Sheets, Thia St Martin, Matthew Labenski, Hormoz Mazdiyasni, Zhendong Zhu et al. "Abstract 4482: Discovery of an irreversible PI3Kα-specific Inhibitor". En Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-4482.

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Carrell, R. W., P. D. Christey y D. R. Boswell. "SERPINS: ANTITHROMBIN AND OTHER INHIBITORS OF COAGULATION AND FIBRINOLYSIS. EVIDENCE FROM AMINO ACID SEQUENCES". En 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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Bennett, Ruth, Merel Gijsen y Anthony Kong. "Abstract 1737: Overcoming trastuzumab resistance with the irreversible Pan-HER inhibitor neratinib". En Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-1737.

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Kaliszczak, Maciej, Meg Perumal y Eric Aboagye. "Abstract 2608: HDAC-C1A: An irreversible HDAC inhibitor with significant anti-tumor activity". En Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2608.

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Venetsanakos, Eleni, Yan Xing, Natalie Loewenstein, J. Michael Bradshaw, Dane Karr, Jacob LaStant, Philip Nunn et al. "Abstract 2091: PRN1371, an irreversible, covalent inhibitor of FGFR1-4 exhibits sustained pathway inhibition in cancer cell lines". En Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-2091.

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Smaill, Jeff B., Jagdish Jaiswal, Maria Abbattista, Guo-Liang Lu, Robert F. Anderson, Amir Ashoorzadeh, William A. Denny et al. "Abstract A247: Mechanism of action of the hypoxia-activated irreversible pan-HER inhibitor SN29966." En Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-a247.

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Ercan, Dalia, Wenjun Zhou, Masahiko Yanagita, Marzia Capelletti, Andrew Rogers, Yun Xiao, Nathanael S. Gray y Pasi A. Janne. "Abstract 4736: Amplification of ERK2 mediates resistance to the novel irreversible EGFR inhibitor WZ4002". En Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-4736.

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Holmes, W. E., H. R. Lijnen y D. Collen. "CHARACTERIZATION OFα2-ANTIPLASMIN.REACTIVE SITE VARIANTS PRODUCED BY SITE-DIRECTED MUTAGENESIS". En XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644766.

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α2-Antiplasmin (α2AP) is the primary physiological plasmin inhibitor in human plasma. The inhibition is rapid (second order rate constants (k1) are expressed as M−1 s−1 ) (k1 = 2 × 107) and occurs as the consequence of an irreversible 1:1 stoichiometric complex formation; the exact nature of and the forces involved in complex formation are not fully understood. In fact, what makes α2AP an inhibitor, rather than simply a substrate remains unresolved. Recently, we deduced the primary structure of α2 AP from the sequence of its cDNA. 95%of this sequence was confirmed by amino acid (aa) sequence analysis of naturalα2 AP (α2 AP)? The 452 aa molecule contains 2 disulfide bonds and 4 glycosylated Asn residues, aa sequence alignment confirmed α2AP's membership in the Serpin family. The reactive site sequence as determined by NH2 - and COOH-terminal aa sequence analysis of the plasmin-modified inhibitor and the released M−r ∼ 8000 peptide is Met362-Ser363-Arg364-Met365-Ser366, P3-P2-P1-P'1-P'2, respectively.Natural and engineered P1 residue substitutions in the Serpin α2 -antitrypsin ( α2 AT) have shown altered specificities and efficiencies. To further examine the role of P and P' residues in determining Serpin specificity, in the present study we have by site-directed mutagenesis, deleted (△) the P'l-Met365 residue of a AP thereby producing a recombinant (r) inhibitor (r α2 AP△Met365) whose putative new reactive site mimics that of antithrombin III (ATIII) and a AT-Pittsburgh (Pl-Arg-P'1-Ser). A second variant was constructed (ra2AP△Arg364) in which the Pl-Arg364 residue was deleted, producing the new sequence Met362-Ser363-Met364-Ser365, containing 2 potential sites analogous to the Pl-P'l, Met-Ser reactive site of α2 AT. The variants and r α2 AP were expressed in CH0 cells, purified and compared with n α2 AP, α2AT and ATIII for the ability to inhibit plasmin, thrombin, trypsin and elastase. n α2 AP and r α2 AP had nearly identical inhibition constants and like ATIII did not inhibit neutrophil elastase. Without heparin both α2 APs and ATIII inhibited thrombin moderately (k1 = 2 to 4× 103 ). Bovine trypsin was neutralized by the α2 APs with k1 = 3 × 106 and by ATIII with k1 = 1 × 105. The α2APs inhibited plasmin (k1 = 2 ×107 ) much more efficiently than ATIII (K1 =2 × 103 ). In contrast, was a highly effective antielastase (k1 = 1 × 107 ), a poor plasmin and thrombin inhibitor ancl inhibited bovine trypsin with = 2 × 10. As reported by others, α2 AT-Pittsburg has greatly reduced antielastase activity and greatly enhanced antithrombin activity. Analysis of ra APAMet365 revealed little change in activity toward plasmin, trypsin and elastase. Thus, α2 AP has no absolute requirement for Met .in the P'l position in order to effectively inhibit plasmin and trypsin. The other P^ subsites appear to be spatially flexible as deletion of the natural P'l residue must displace them. Contrary to prediction a 20-fold decrease in antithrombin activity was observed rather than an enhanced activity. Analysis of rα2 AP△Arg364 showed that it is unreactive with plasmin, trypsin and thrombin, but that it has acquired a significant antielastase activity (k1 = 1.5 × 105). The exact PI residue(s) has not been determined but removal of the bulky basic Arg364 may have resulted in accessibility of the predicted reactive site(s) peptide bond(s) Met362-Ser363 or Met364-Ser365 to the active site cleft of elastase. α2AP'Enschede', a natural mutant with deficient antiplasmin activity, was shown to contain an Ala insertion between aa 353 and 357, 7 to 10 positions NH2-terminal to its reactive site (Holmes et al., this meeting). This mutation results in conversion of α2 AP'Enschede' from an inhibitor to a substrate that retains a high affinity for the active site of plasmin.

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Informes sobre el tema "Irreversible inhibitor"

Terskikh, Alexey V. Development of Irreversible Inhibitors of MELK Kinase. Fort Belvoir, VA: Defense Technical Information Center, agosto de 2008. http://dx.doi.org/10.21236/ada492687.

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Ohad, Itzhak y Himadri Pakrasi. Role of Cytochrome B559 in Photoinhibition. United States Department of Agriculture, diciembre de 1995. http://dx.doi.org/10.32747/1995.7613031.bard.

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The aim of this research project was to obtain information on the role of the cytochrome b559 in the function of Photosystem-II (PSII) with special emphasis on the light induced photo inactivation of PSII and turnover of the photochemical reaction center II protein subunit RCII-D1. The major goals of this project were: 1) Isolation and sequencing of the Chlamydomonas chloroplast psbE and psbF genes encoding the cytochrome b559 a and b subunits respectively; 2) Generation of site directed mutants and testing the effect of such mutation on the function of PSII under various light conditions; 3) To obtain further information on the mechanism of the light induced degradation and replacement of the PSII core proteins. This information shall serve as a basis for the understanding of the role of the cytochrome b559 in the process of photoinhibition and recovery of photosynthetic activity as well as during low light induced turnover of the D1 protein. Unlike in other organisms in which the psbE and psbF genes encoding the a and b subunits of cytochrome b559, are part of an operon which also includes the psbL and psbJ genes, in Chlamydomonas these genes are transcribed from different regions of the chloroplast chromosome. The charge distribution of the derived amino-acid sequences of psbE and psbF gene products differs from that of the corresponding genes in other organisms as far as the rule of "positive charge in" is concerned relative to the process of the polypeptide insertion in the thylakoid membrane. However, the sum of the charges of both subunits corresponds to the above rule possibly indicating co-insertion of both subunits in the process of cytochrome b559 assembly. A plasmid designed for the introduction of site-specific mutations into the psbF gene of C. reinhardtii. was constructed. The vector consists of a DNA fragment from the chromosome of C. reinhardtii which spans the region of the psbF gene, upstream of which the spectinomycin-resistance-conferring aadA cassette was inserted. This vector was successfully used to transform wild type C. reinhardtii cells. The spectinomycin resistant strain thus obtained can grow autotrophically and does not show significant changes as compared to the wild-type strain in PSII activity. The following mutations have been introduced in the psbF gene: H23M; H23Y; W19L and W19. The replacement of H23 involved in the heme binding to M and Y was meant to permit heme binding but eventually alter some or all of the electron transport properties of the mutated cytochrome. Tryptophane W19, a strictly conserved residue, is proximal to the heme and may interact with the tetrapyrole ring. Therefore its replacement may effect the heme properties. A change to tyrosine may have a lesser affect on the potential or electron transfer rate while a replacement of W19 by leucine is meant to introduce a more prominent disturbance in these parameters. Two of the mutants, FW19L and FH23M have segregated already and are homoplasmic. The rest are still grown under selection conditions until complete segregation will be obtained. All mutants contain assembled and functional PSII exhibiting an increased sensitivity of PSII to the light. Work is still in progress for the detailed characterization of the mutants PSII properties. A tobacco mutant, S6, obtained by Maliga and coworkers harboring the F26S mutation in the b subunit was made available to us and was characterized. Measurements of PSII charge separation and recombination, polypeptide content and electron flow indicates that this mutation indeed results in light sensitivity. Presently further work is in progress in the detailed characterization of the properties of all the above mutants. Information was obtained demonstrating that photoinactivation of PSII in vivo initiates a series of progressive changes in the properties of RCII which result in an irreversible modification of the RCII-D1 protein leading to its degradation and replacement. The cleavage process of the modified RCII-D1 protein is regulated by the occupancy of the QB site of RCII by plastoquinone. Newly synthesized D1 protein is not accumulated in a stable form unless integrated in reassembled RCII. Thus the degradation of the irreversibly modified RCII-D1 protein is essential for the recovery process. The light induced degradation of the RCII-D1 protein is rapid in mutants lacking the pD1 processing protease such as in the LF-1 mutant of the unicellular alga Scenedesmus obliquus. In this case the Mn binding site of PSII is abolished, the water oxidation process is inhibited and harmful cation radicals are formed following light induced electron flow in PSII. In such mutants photo-inactivation of PSII is rapid, it is not protected by ligands binding at the QB site and the degradation of the inactivated RCII-D1 occurs rapidly also in the dark. Furthermore the degraded D1 protein can be replaced in the dark in absence of light driven redox controlled reactions. The replacement of the RCII-D1 protein involves the de novo synthesis of the precursor protein, pD1, and its processing at the C-terminus end by an unknown processing protease. In the frame of this work, a gene previously isolated and sequenced by Dr. Pakrasi's group has been identified as encoding the RCII-pD1 C-terminus processing protease in the cyanobacterium Synechocystis sp. PCC 6803. The deduced sequence of the ctpA protein shows significant similarity to the bovine, human and insect interphotoreceptor retinoid-binding proteins. Results obtained using C. reinhardtii cells exposes to low light or series of single turnover light flashes have been also obtained indicating that the process of RCII-D1 protein turnover under non-photoinactivating conditions (low light) may be related to charge recombination in RCII due to back electron flow from the semiquinone QB- to the oxidised S2,3 states of the Mn cluster involved in the water oxidation process.

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