Dissertations / Theses: 'Inhibitors'

1

Miyazaki, Hiroshi. "Studies on Inhibitors of Plasminogen Activator Inhibitor-1(PAI-1) and Inhibitors of PAI-1 Production as Antithrombotic Agents." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/126818.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Bodhe, A. M. "Enzyme inhibitors." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 1988. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/3302.

Full text

APA, Harvard, Vancouver, ISO, and other styles

3

Rioja, Alphonso Sid. "Synthesis of prenyl transferase inhibitors and histone deacetylase inhibitors." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418246.

Full text

APA, Harvard, Vancouver, ISO, and other styles

4

Trivedi-Parmar, Vinay. "Synthesis and Optimization of Non-Phenolic Inhibitors of Macrophage Migration Inhibitory Factor." Thesis, Yale University, 2019. http://pqdtopen.proquest.com/#viewpdf?dispub=13851921.

Full text

Abstract:

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and an upstream regulator of inflammation and cell proliferation. Interestingly, MIF is also an enzyme that functions as a keto-enol tautomerase, though this function is believed to be vestigial in humans. Implicated in the pathogenesis of multiple infectious and autoimmune diseases, including rheumatoid arthritis and cancer, MIF has emerged as an attractive drug target, with the tautomerase active site serving as a convenient binding pocket for small molecule inhibitors. Most MIF inhibitors include a phenol ring, which forms an essential hydrogen bond with an asparagine residue at the back of the binding pocket. While phenol is not an uncommon moiety in approved dugs, it is particularly susceptible to rapid phase 11 metabolic processes and excretion from biological systems, resulting in low oral bioavailability and short half-life. Therefore, potent non-phenolic MIF inhibitors are desirable. Two series of MIF inhibitors lacking the commonly employed phenol group were pursued and are described in this thesis.

The first was a series of benzoxazolone inhibitors. Attempts at lead optimization were stymied by sensitivity of tautomerase assay results to protein source and incubation conditions, inconsistencies between molecular modeling studies and experimental activity data, and the inability to obtain a crystal structure of the protein–inhibitor complex. A binding mode could not be resolved for the scaffold, preventing a rational, structure-based approach to drug development. Nevertheless, a methodical medicinal chemistry strategy was employed to elaborate the structure-activity relationships (SAR) of the series and discover potent inhbitors. A circa 5 µM inhibitor was obtained, but when further attempts to optimize the series proved ineffective, attention was turned to a new scaffold.

The second series of MIF inhibitors pursued involved bioisosteric replacement of phenol with a pyrazole, which is capable of forming dual hydrogen bonds with the asparagine residue at the back of the binding pocket. From a 113-µM virtual screening hit, a structure-based, computer-aided lead optimization strategy was employed. X-ray crystal structures of MIF-inhibitor complexes and molecular modeling results guided effective selection and placement of substituents on the scaffold. Methodical derivitization and expansion of the scaffold to include auxiliary aryl functionality near the rim of the binding pocket and recognition of the benefit of pyrazole fluorination were essential breakthroughs in optimizing this series, resulting in inhibitors with potencies around 60-70 nm. From a metabolic perspective, bioisosteric replacement of a salt bridge-forming carboxylate group on the scaffold with a pharmacologically favorable sulfonamide was found to be well tolerated. Additionally, modification of the solvent-exposed region of the scaffold with solubilizing groups was shown to improve aqueous solubility without affecting activity. The pyrazoles are the only the second series of MIF inhibitors to be optimized from an initial screening hit to give inhibitors with nanomolar potency. With their high potencies and expected favorable metabolism, compounds in this series have the potential to be developed into true MIF-directed therapeutics.

APA, Harvard, Vancouver, ISO, and other styles

5

Mamone, Marius. "N-fluoroalkyles et CF3-cyclopropanes; vers de nouvelles unités peptidomimétiques." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS276.

Full text

Abstract:

Grâce à des propriétés physico-chimiques particulières, le fluor prend de plus en plus d’importance dans la chimie médicinale et plus particulièrement dans les peptidomimétiques. Dans ce mémoire, deux classes de peptidomimétiques fluorées ont été étudiées.Dans la première partie, de nouveaux groupements N-Rf ; les hydrazines difluoro ou trifluorométhylées et les 1,2,3 triazoles N-difluorométhylés ont été préparés et des études de leurs propriétés structurales ont montré l’intérêt de l’incorporation du fluor sur la conformation des pseudopeptides via des interactions NH-F.Dans la seconde partie, de nouveaux peptidomimétiques comportant des groupements cyclopropanes trifluorométhylés ont été conçus et synthétisés en tant qu’inhibiteurs potentiels du protéasome 26S (un macro-complexe protéique impliqué dans la dégradation de nombreuses protéines intracellulaires et qui a fait ses preuves en tant que cible pour le traitement de cancers)
Through special physico-chemical properties, fluorine is becoming increasingly important in medicinal chemistry and particularly in peptidomimetics. In this paper, two classes of fluorinated peptidomimetics were studied.In the first part, new N-Rf moieties; difluoro or trifluoromethylated hydrazines and N-difluoromethyl 1,2,3 triazoles were prepared and the study of their structural properties have shown the benefit of the incorporation of fluorine on the conformation of the peptidomimetics via NH-F interactions.In the second part, new trifluoromethylated cyclopropanes containing peptidomimetics were designed and synthesized as potential inhibitors of the 26S proteasome, a macro-complex protein involved in the degradation of many intracellular proteins and which has been recognized as a target for cancer treatment

APA, Harvard, Vancouver, ISO, and other styles

6

Paren, Helen. "Inhibitors of metalloproteases." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260150.

Full text

APA, Harvard, Vancouver, ISO, and other styles

7

Tan, Swee Hain. "Organic corrosion inhibitors." Thesis, Tan, Swee Hain (1991) Organic corrosion inhibitors. PhD thesis, Murdoch University, 1991. https://researchrepository.murdoch.edu.au/id/eprint/333/.

Full text

Abstract:

The overall aims of this thesis were to conduct a broad survey of possible organic corrosion inhibitors in near-neutral chloride solutions and to elucidate the mechanisms of such action. Altogether, 130 organic compounds were studied as possible corrosion inhibitors for pure iron, mild steel, copper and aluminium in aerated near-neutral (pH = 8.4) solutions containing 500 ppm NaCl and 100 ppm NaHCO, conditions often encountered in water-based automotive engine coolants. Inhibitor behaviour was investigated using steady-state electrochemical techniques including polarisation curves, Stern-Geary and corrosion potential (Em,) measurements. The organic compounds examined were found to be highly specific in their inhibitive action toward the metals studied. Typical examples of highly effective corrosion inhibitors were: sebacate and octanoate for pure iron; oleate and sebacate for mild steel; benzotriazole and 2-mercaptobenzothiazole for copper; and laurate and oleate for aluminium. E, was found to provide a rapid and convenient screening test for evaluating the inhibitor performance of organic compounds toward pure iron, mild steel and aluminium but was less useful for copper. Good organic inhibitors were found to act as anodic inhibitors toward pure iron and mild steel but as anodic or mixed-type inhibitors toward copper. For aluminium, the majority of the compounds studied were found to act as anodic inhibitors. However,However, it was also found that only pit initiation was inhibited, i.e. existing pits were not prevented from developing. Optical microscopy of pitted aluminium surfaces indicated their nature varied considerably with inhibition efficiency. The role of complex formation in organic corrosion inhibitors was found to vary with the metal. Complexation of either iron(I1) or iron(II1) ions was found to have an insignificant effect on mild steel. The corrosion rate of copper was found to increase with the copper(LI) complex stability, thus indicating complex formation to be the rate-determining step. For aluminium, the observed effects were found to depend on complex stability. For weak to moderate complexants, inhibitor efficiency (measured as E,,) increased with increasing complexation. However, very strong complexing agents were sufficiently stable to dissolve the aluminium oxide surface, leading to poor inhibition. Aluminium pit morphology was found, using scanning electron microscopy, to change from hemispherical in the uninhibited solution to irregular in the presence of complexing inhibitors. No simple relationships between inhibitor efficiency and molecular structure were found. However, carbon chain length, the nature of functional group(s) and their location in the molecule were found to be important but varied according to the metal. The inhibiting ability of sebacate (a straight chain C, dicarboxylate) was found not to be compromised by water movement (stirring) or pre-existing corrosion product layers. Immersion tests showed that passive film formation on mild steel in sebacate solution involved two stages and was complete only after -100 h immersion. The ion selective properties of several iron(II1) carboxylates and hydrated iron(II1) oxide films were studied by membrane potential measurements in neutral sodium chloride solutions. Some specimens were also studied by Mossbauer spectroscopy. These results show that dicarboxylates are good inhibitors toward mild steel because they form impermeable films. Poor inhibitor performance is associated with the anion selectivity of the film which in turn appears to be related to the film purity. A model is suggested for the inhibition mechanism of mild steel corrosion by dicarboxylates in aerated near-neutral chloride solutions.

APA, Harvard, Vancouver, ISO, and other styles

8

Tan, Swee Hain. "Organic corrosion inhibitors." Murdoch University, 1991. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20060818.150145.

Full text

Abstract:

The overall aims of this thesis were to conduct a broad survey of possible organic corrosion inhibitors in near-neutral chloride solutions and to elucidate the mechanisms of such action. Altogether, 130 organic compounds were studied as possible corrosion inhibitors for pure iron, mild steel, copper and aluminium in aerated near-neutral (pH = 8.4) solutions containing 500 ppm NaCl and 100 ppm NaHCO,, conditions often encountered in water-based automotive engine coolants. Inhibitor behaviour was investigated using steady-state electrochemical techniques including polarisation curves, Stern-Geary and corrosion potential (Em,) measurements. The organic compounds examined were found to be highly specific in their inhibitive action toward the metals studied. Typical examples of highly effective corrosion inhibitors were: sebacate and octanoate for pure iron; oleate and sebacate for mild steel; benzotriazole and 2-mercaptobenzothiazole for copper; and laurate and oleate for aluminium. E, was found to provide a rapid and convenient screening test for evaluating the inhibitor performance of organic compounds toward pure iron, mild steel and aluminium but was less useful for copper. Good organic inhibitors were found to act as anodic inhibitors toward pure iron and mild steel but as anodic or mixed-type inhibitors toward copper. For aluminium, the majority of the compounds studied were found to act as anodic inhibitors. However,However, it was also found that only pit initiation was inhibited, i.e. existing pits were not prevented from developing. Optical microscopy of pitted aluminium surfaces indicated their nature varied considerably with inhibition efficiency. The role of complex formation in organic corrosion inhibitors was found to vary with the metal. Complexation of either iron(I1) or iron(II1) ions was found to have an insignificant effect on mild steel. The corrosion rate of copper was found to increase with the copper(LI) complex stability, thus indicating complex formation to be the rate-determining step. For aluminium, the observed effects were found to depend on complex stability. For weak to moderate complexants, inhibitor efficiency (measured as E,,) increased with increasing complexation. However, very strong complexing agents were sufficiently stable to dissolve the aluminium oxide surface, leading to poor inhibition. Aluminium pit morphology was found, using scanning electron microscopy, to change from hemispherical in the uninhibited solution to irregular in the presence of complexing inhibitors. No simple relationships between inhibitor efficiency and molecular structure were found. However, carbon chain length, the nature of functional group(s) and their location in the molecule were found to be important but varied according to the metal. The inhibiting ability of sebacate (a straight chain C, dicarboxylate) was found not to be compromised by water movement (stirring) or pre-existing corrosion product layers. Immersion tests showed that passive film formation on mild steel in sebacate solution involved two stages and was complete only after -100 h immersion. The ion selective properties of several iron(II1) carboxylates and hydrated iron(II1) oxide films were studied by membrane potential measurements in neutral sodium chloride solutions. Some specimens were also studied by Mossbauer spectroscopy. These results show that dicarboxylates are good inhibitors toward mild steel because they form impermeable films. Poor inhibitor performance is associated with the anion selectivity of the film which in turn appears to be related to the film purity. A model is suggested for the inhibition mechanism of mild steel corrosion by dicarboxylates in aerated near-neutral chloride solutions.

APA, Harvard, Vancouver, ISO, and other styles

9

Menon, V. "Molecular and functional aspects of hydrolyases / inhibitors with emphasis on aspartic protease inhibitor." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2012. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2401.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Hirst, Claire Elizabeth 1971. "Tissue distribution and regulation of the granzyme B inhibitor, proteinase inhibitor 9." Monash University, Dept. of Biochemistry and Molecular Biology, 2002. http://arrow.monash.edu.au/hdl/1959.1/8488.

Full text

APA, Harvard, Vancouver, ISO, and other styles

11

Darkins, Paul Anthony. "Synthesis and enzyme inhibitory properties of novel proteinase inhibitors derived from enantiopure #alpha#-diazoketones." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318839.

Full text

APA, Harvard, Vancouver, ISO, and other styles

12

Croxford, J. Ludovic. "Gene therapy for experimental allergic encephalomyelitis by delivery of inhibitory cytokines or cytokine inhibitors." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314201.

Full text

APA, Harvard, Vancouver, ISO, and other styles

13

Nakahira, Marcel. "Caracterização físico-química e estrutural do SbKI, um inibidor de serinoproteases de sementes de barbatimão (Stryphnodendron barbatiman)." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-01042014-174549/.

Full text

Abstract:

Os inibidores de proteases desempenham nas plantas funções como: defesa contra ataque de predadores de sementes, regulação de enzimas endógenas e fontes de proteínas e aminoácidos. Muitos destes inibidores são utilizados em estudos bioquímicos, bem como no tratamento de patologias humanas como inflamação e câncer. Neste trabalho, um inibidor de serinoprotease, presente na semente de Stryphnodendron barbatinan (barbatimão), foi purificado, caracterizado e denominado SbKI. Sementes de barbatimão maduras foram trituradas, até a obtenção de uma farinha, e esta foi suspensa em PBS, pH 7,4 (1 :5 m/v), sob agitação por 14 horas a 4°C. O extrato foi centrifugado, filtrado e tratado com PVPP, sendo denominado EB, o qual apresentou inibição da coagulação sanguínea e da atividade de algumas serinoproteases. O inibidor SbKI foi purificado utilizando-se três procedimentos cromatográficos: cromatografia de exclusão molecular (Superdex-75, 10/30), troca iônica (Mono-S HR, 5/5), ambas acopladas em um sistema &TA Purifier e fase reversa (C-18, Waters 250 x 4,6mm) acoplada a um sistema HPLC. Em cada etapa de purificação a presença do inibidor foi monitorada pelos testes de atividade inibitória da tripsina e da coagulação, ambos in vitro. SDS-PAGE, sob condições redutoras, mostrou que o inibidor é formado por duas cadeias polipeptídicas (cadeia pesada e leve) unida por ligação dissulfeto. As cadeias foram separadas pela cromatografia de &se reversa após serem reduzidas e alquiladas. Suas seqüências N-terminais foram determinadas pela degradação de Edman, em seqüenciador automatizado, apresentando alta identidade seqüencial com inibidores do tipo Kunitz de outras leguminosas. A determinação da massa/molecular do inibidor e de suas cadeias isoladas, foram determinadas por espectroscopia de massa (LCtESI-MS system) mostrando massas moleculares de 19.570Da7 15530Da e 4040Da, respectivamente. A espectroscopia de dicroísmo circular (CD) revelou que o inibidor é formado predominantemente por elementos beta e estruturas desordenadas. SbKI foi estável a variações de pHs (2-12) e temperaturas extremas e a temperatura de transição foi calculada em 73,3\" C. A determinação das constantes de inibição (KI) foi realizada para as serinoproteases tripsina (KI = 5,5 nM) e calicreína plasmática (KI = 1,l nM).
Proteinase inhibitors perform many beneficia1 roles in plants such as defense against the attack of seed predators, regulation of endogenous enzymes and sources of proteins and amino acids. Many inhibitors are used in biochemistry research, as well as human pathology treatment such as inflammation and cancer. In this work, a serino proteinase inhibitor found in Stryphnodendron barbatiman seeds (barbatimão) was purified, characterized and denoted SbKI. Mature barbatimão seeds were ground and suspended in PBS pH 7.4 (15 wlv) and stirred for 14 hours at 4OC. The suspension was centrifuged, filtered and treated with PVPP and denoted EB. This EB inhibited blood coagulation and some serine proteinases activities. The inhibitor SbKI was purified by three chromatography step: molecular exclusion (on Supredex-75, 10/30), ion exchange (on Mono-S, 5/5), both connected to AKTA Purifíer System and reversed phase (on C-18, Waters 250 x 4.6 mm) connected to HPLC System. In each purification step the presence of inhibitor was monitored, in vitro, by trypsin and coagulation inhibitory activity. SDS-PAGE, reduced conditions, showed two polypeptide chains (heavy and light chains) linked by one disulphide bridge. The chains were separated by reversed phase chromatography aíter reduced and alquilated. The N-terminal sequence were performed on automated protein sequencer by Edman degradation and showed homology with Kunitz type inhibitors from Leguminosae. Molecular weight of inhibitor and its chains were determined by mass spectrometry (LC/ESI-MS System) and showed molecular weight of 19.570Da, 15.530Da and 4040Da, respectively. Circular dichroism spectroscopy showed SbKI is constituted predominantly by P elements and unordered structures. SbKI was stable over extreme ranges of pH (2-12) and temperature and the transition temperature 73.3\"C investigated by CD and fluorescence emission spectroscopies. Inhibition constants (Ki) were determined by typsin (Ki = 5.5 nM) and human plasmatic kallikrein (Ki = 1.1 mM)

APA, Harvard, Vancouver, ISO, and other styles

14

McNamara, Anne. "Potentiation of Topoisomerase I inhibitors by Hsp90 inhibitors: Mechanistic and Functional studies." Thesis, University of Liverpool, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485908.

Full text

Abstract:

Purpose: Inhibitors of topoisomerase I are of considerable biomedical importance as they are the sole target of the camptothecin family of anticancer drugs. Camptothecin derivatives are routinely used in cancer treatment however these drugs are highly toxic and tumour cells can develop drug resistance. It is therefore essential that new treatment strategies are investigated. The aim of this study was to use a rational approach previously developed by our group to enhance the efficacy of topoisomerase I inhibitors. Objectives: Previous work in our group identified Hsp90 as a topoisomerase II interacting protein. The combination of a topoisomerase II poison and . Hsp90 inhibitor were found to act synergistically in human cancer cell lines. We proposed that topoisomerase I and Hsp90 inhibitors would also. synergistically interact. The p53 isogenic pair HCT116 human colon adenomacarcinoma cell line were used to dissect the mechanism behind the synergy. Results: Hsp90 inhibitors interact synergistically with topoisomerase I inhibitors in causing inhibition of cell growth and survival in the p53-isogenic pair HCT116 human colon adenocarcinoma cell line. The mode of cell death induced by the combination treatment was determined as apoptotic which was synergistically enhanced in the combined treatment compared to the drugs alone. p53 deficient cells were significantly more sensitive to the combined treatment initiating apoptosis'16 hours post treatment compared to 24 hours in p53 WT cells. The synergistic increase in apoptosis was not caused by increased topoisomerase mediated-DNA damage in either the p53 KO or WT cell lines. Dual Hsp90 and topoisomerase I inhibition selectively abrogated the G2/M checkpoint in p53 deficient cells. p53 WT cells maintained both Sand G2/M checkpoint integrity. We propose that abrogation of the G2/M checkpoint was responsible for the enhanced sensitivity of p53 KO cells to the combined treatment, and that an underlying mechanism was responsible for the synergy observed in both p53 WT and KO cells. Inhibition of Hsp90 caused levels of the anti-apoptotic protein, Bcl2 to decline. Bcl2 loss was associated with a corresponding increase in caspase-3 activation following combined treatment with Hsp90 and topoisomerase I inhibitors. This phenomenon was observed in both p53 WT and KO cell lines. We propose that inhibition of Hsp90 mediated loss of Bcl2 function, resulting in enhanced caspase-3 activation and apoptosis, and that this underlying general mechanism of synergy applies to both p53 WT and KO cell lines. Conclusion: We have developed a rational, mechanism based anticancer drug therapy using Hsp90 and topoisomerase I inhibitors in combination. p53 deficient cells were significantly more sensitive to this treatment caused by selective abrogation of the G2IM checkpoint in these cells. We therefore predict that this treatment may be more effective in patients with p53 deficient or mutant tumours. Based on this study and previous studies in our group, combined Hsp90 and topoisomerase I inhibitor therapy has been put forward as a clinical based trial.

APA, Harvard, Vancouver, ISO, and other styles

15

Gangadharan, Komala Muralikrishna. "The Role of SGLT2 Inhibitors and DPP4 Inhibitors in Preventing Diabetic Nephropathy." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/15925.

Full text

Abstract:

Diabetic nephropathy is the most common cause of end stage kidney disease in the world. Newer diabetic medications have arrived over the last few years. However there is lack of experimental and clinical evidence in favour of better outcomes. The two most important drug categories that have emerged in this century are the dipeptidyl peptidase-4 inhibitors DPP4 inhibitors (DPP4i) and sodium glucose cotransporter inhibitors (SGLT2i). Their role in preventing diabetic nephropathy irrespective of their glycaemic benefits is unknown. The aim of our project was to demonstrate the renoprotective benefits of these medications. In this thesis we used endothelial nitric oxide synthase knock out (eNOS -/-) mice and induced type 1 diabetes using streptozotocin (STZ) injection. We studied the changes of diabetic nephropathy in these mice including clinical outcomes, biochemical changes, inflammatory and fibrotic pathways. Our study with empagliflozin showed that SGLT2 inhibitors might not have a beneficial role in preventing diabetic nephropathy when blood glucose levels were high. We studied the role of linagliptin, a DPP4i, in preventing the interaction between DPP4 and cation independent mannose-6-phosphate receptor (CIM6PR) in the setting of high glucose in an in vitro model using kidney proximal tubular cells. Our results showed that linagliptin reduced the interaction between DPP4 and CIM6PR possibly resulting in the prevention of activation of latent TGFß. We proved this subsequently in an in vivo model of STZ induced type 1diabetes in eNOS -/- mice using linagliptin and another DPP4i, saxagliptin. We demonstrated that these DPP4i were able to reduce tubulointerstitial fibronectin deposition and demonstrated reduced expression of pSmad2/3, a downstream marker of TGFß activation. Hence our studies have helped in partly identifying the puzzle of diabetic nephropathy and provide some answers on the role of newer anti diabetic agents in preventing it.

APA, Harvard, Vancouver, ISO, and other styles

16

Lehle, Karla, Stephan Schreml, Leoni A. Kunz-Schughart, Leopold Rupprecht, Dietrich E. Birnbaum, Christof Schmid, and Jürgen G. Preuner. "mTOR Inhibitors and Calcineurin Inhibitors Do Not Affect Adhesion Molecule Expression of Human Macro- and Microvascular Endothelial Cells." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-135401.

Full text

Abstract:

We examined the effect of cyclosporin A, tacrolimus, sirolimus and everolimus on the cell growth, viability, proliferation, expression of cellular adhesion molecules (CAM) and leukocyte (PBMC) binding of human macrovascular (coronary artery, saphenous vein) and microvascular endothelial cells (EC). Tacrolimus did not affect EC integrity, growth or expression of CAM. Exclusively, EC from the coronary arteries showed a reduced cellular growth (about 30%) under cyclosporin A and tacrolimus treatment. In contrast, treatment with mTOR inhibitors reduced EC proliferative activity by about 40%, independently of the EC origin. No induction of apoptosis (caspase-3/7 activity) or cytotoxicity (MTS test) was observed. Long-term treatment with high concentrations of sirolimus and everolimus did not enhance the expression of CAM. Stimulation with tumor necrosis factor significantly increased the expression of CAM, independently of the drugs used. None of the mTOR inhibitors influenced the tumor necrosis factor-induced expression of CAM, whereas adhesion of PBMC increased significantly, as described by other papers. In summary, neither calcineurin inhibitors nor mTOR inhibitors activate human micro- and macrovascular EC. Therefore, the investigated drugs are unlikely to contribute to EC activation during transplant-associated vasculopathy
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

APA, Harvard, Vancouver, ISO, and other styles

17

Benabdi, Sarah. "Inhibition des facteurs d’échange nucléotidique par de petites molécules." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS472.

Full text

Abstract:

Les petites GTPases de la famille Arf sont des régulateurs majeurs du trafic cellulaire. Ils participent à presque tous les aspects de ce processus. Il existe cinq familles d'ArfGEFs chez les eucaryotes, responsables de l'activation des Arfs au sein des membranes. Ces Arfs GEFs partagent un domaine Sec7 catalytique conservé mais aussi des domaines de régulation qui interviennent soit dans des interactions avec des protéines ou des interactions avec des membranes. L'un des moyens d'étudier la fonction des Arfs et leur régulation par les ArfGEFs repose sur l'utilisation de l'inhibition par de petiotes molécules chimiques. La BFA est le premier inhibiteur d'ArfGEF à avoir été identifié et a permis d'identifier de nombreuses fonctions du trafic. D'autres composés ont été identifiés par différentes méthodes de criblage mais leur spécificité in vitro reste peu caractérisée, ce qui peut être un obstacle à une bonne interprétation des observations que l'on en fait en Biologie cellulaire. L'objectif de ce travail a été d'évaluer in vitro la spécificité de chaque petite molécule sur un ensemble de famille d'ArfGEFs en solution et pour la première en présence de membranes artificielles
Small GTPases of the Arf family are major regulators of almost every aspect of membrane traffic in cells. In eukaryotes, five subfamilies of guanine nucleotide exchange factors (ArfGEFs) activate them on different membranes by combining a conserved Sec7 domain, which stimulate the GDP/GTP exchange, and distinct regulatory and membrane binding domains (reviewed in [1]). The identification of the natural compound Brefeldin A as the first known GEF inhibitor, which inhibits Arf functions at the Golgi, established the Arf machinery as model systems to investigate the druggability of small GTPases and their GEFs in diseases. Chemical compounds of unrelated structure have been reported by us and others to inhibit ArfGEF subfamilies. Some of them, recently discovered, remain poorly characterized in vitro, which hampers their use as relevant biological tools. Here, we compared the efficiency and specificity of these inhibitors towards representative members of the major ArfGEF subfamilies using highly purified recombinant proteins reconstituted in artificial membranes

APA, Harvard, Vancouver, ISO, and other styles

18

García, Reyes Balbina [Verfasser]. "Validation of new Casein Kinase 1 (CK1) small molecule inhibitor compounds and characterization of Inhibitors of Wnt Production (IWPs) as inhibitors of CK1δ / Balbina García Reyes." Ulm : Universität Ulm, 2018. http://d-nb.info/1151938424/34.

Full text

APA, Harvard, Vancouver, ISO, and other styles

19

Tiew, Kok-Chuan. "Dengue virus protease inhibitors." Thesis, Wichita State University, 2011. http://hdl.handle.net/10057/6117.

Full text

Abstract:

Dengue virus (DENV) is a major health threat that affects 2.5 billion people, or 40% of the world’s population. However, there are no approved antiviral drugs or vaccines to treat Dengue infection. This thesis describes the design, synthesis and discovery of a new class of inhibitors of DENV NS3 protease. Structure-activity relationship studies have been carried out in order to delineate the structural elements responsible for the activity of this series of compounds. A lead compound suitable for further development has been identified.
Thesis (M.S.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry.

APA, Harvard, Vancouver, ISO, and other styles

20

Houssain, Feroza. "Inhibitors of lignin peroxidase." Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283289.

Full text

APA, Harvard, Vancouver, ISO, and other styles

21

Kraunsoe, James A. E. "Inhibitors of serine proteinases." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318814.

Full text

APA, Harvard, Vancouver, ISO, and other styles

22

Carpenter, Neil M. "Studies on glycosidase inhibitors." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236101.

Full text

APA, Harvard, Vancouver, ISO, and other styles

23

Barnett, Anna L. "Baculovirus inhibitors of apoptosis." Thesis, Oxford Brookes University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388865.

Full text

APA, Harvard, Vancouver, ISO, and other styles

24

Mullan, Elaine L. "Inhibitors of monoamine oxidase." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337116.

Full text

APA, Harvard, Vancouver, ISO, and other styles

25

Levett, Philip Charles. "New electron transport inhibitors." Thesis, University of Nottingham, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357948.

Full text

APA, Harvard, Vancouver, ISO, and other styles

26

Forsberg, Elin. "SCREENING FOR IRF5 INHIBITORS." Thesis, Örebro universitet, Institutionen för naturvetenskap och teknik, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-94629.

Full text

Abstract:

Interferon regulatory factor 5 (IRF5) is a protein with different functions including theactivation of genes that encode different cytokines. Overexpression of IRF5 has been observedto lead to different types of stress in the cells, including an overproduction of cytokines, whichis referred to as a cytokine storm. Clinical states in which dysregulated cytokine release in theform of a cytokine storm can be referred to with an umbrella term: Cytokine storm syndrome.The aim of this study was to test for inhibitors for IRF5 that could be developed and used as apharmaceutical drug to treat Cytokine Storm Syndromes including autoimmune diseases andCOVID-19. The method for this screeing consisted of finding possible inhibitors usingcomputer based drug design which resulted in the selection of 21 possible inhibitors. Thesesubstances were then tested on induced macrophages that are cytokine producing. The abilityfor inhibition is based on the amount of cytokines present in the sample after exposure. Thiswas tested using an ELISA based assay which measures the amount of cytokines in the sample..A handful of substances was found to be effective and substances 11 and 17 stood out asespecially effective. This indicates the possibitily for a drug to be developed that would inhibitIRF5, which could be used for treatment of cytokine storm syndromes.Keywords: IRF5,

APA, Harvard, Vancouver, ISO, and other styles

27

Lubchak, I. V., and A. Koneva. "Inhibitors for cholesterol reduction." Thesis, Sumy State University, 2016. http://essuir.sumdu.edu.ua/handle/123456789/45956.

Full text

Abstract:

Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels. Many of them involve atherosclerosis, which causes most heart attacks and strokes. Cardiovascular diseases are the leading cause of death globally. Nearly 2,200 Americans die of cardiovascular disease daily, with an average of one death occurring every 40 seconds. However, elevated levels of certain forms of cholesterol are some of the primary drivers in the development of some CVDs.

APA, Harvard, Vancouver, ISO, and other styles

28

Boucher, Raymond John. "Approaches to lipoxygenase inhibitors." Thesis, University of Bath, 1987. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378445.

Full text

APA, Harvard, Vancouver, ISO, and other styles

29

Abe, Mineo. "Development of peptide inhibitors of the receptor tyrosine kinase activity in a novel inhibitory mechanism." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/120515.

Full text

APA, Harvard, Vancouver, ISO, and other styles

30

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.

Full text

Abstract:

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.

APA, Harvard, Vancouver, ISO, and other styles

31

Lehle, Karla, Stephan Schreml, Leoni A. Kunz-Schughart, Leopold Rupprecht, Dietrich E. Birnbaum, Christof Schmid, and Jürgen G. Preuner. "mTOR Inhibitors and Calcineurin Inhibitors Do Not Affect Adhesion Molecule Expression of Human Macro- and Microvascular Endothelial Cells." Karger, 2008. https://tud.qucosa.de/id/qucosa%3A27646.

Full text

Abstract:

We examined the effect of cyclosporin A, tacrolimus, sirolimus and everolimus on the cell growth, viability, proliferation, expression of cellular adhesion molecules (CAM) and leukocyte (PBMC) binding of human macrovascular (coronary artery, saphenous vein) and microvascular endothelial cells (EC). Tacrolimus did not affect EC integrity, growth or expression of CAM. Exclusively, EC from the coronary arteries showed a reduced cellular growth (about 30%) under cyclosporin A and tacrolimus treatment. In contrast, treatment with mTOR inhibitors reduced EC proliferative activity by about 40%, independently of the EC origin. No induction of apoptosis (caspase-3/7 activity) or cytotoxicity (MTS test) was observed. Long-term treatment with high concentrations of sirolimus and everolimus did not enhance the expression of CAM. Stimulation with tumor necrosis factor significantly increased the expression of CAM, independently of the drugs used. None of the mTOR inhibitors influenced the tumor necrosis factor-induced expression of CAM, whereas adhesion of PBMC increased significantly, as described by other papers. In summary, neither calcineurin inhibitors nor mTOR inhibitors activate human micro- and macrovascular EC. Therefore, the investigated drugs are unlikely to contribute to EC activation during transplant-associated vasculopathy.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

APA, Harvard, Vancouver, ISO, and other styles

32

Fraser, Rebecca Dawn. "Isolation of natural product inhibitors and synthesis of inhibitors of signal transduction : Part II structure-activity relationship for a series of glycosidase inhibitors." Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/30508.

Full text

APA, Harvard, Vancouver, ISO, and other styles

33

Abbott, Belinda Maree 1976. "Synthesis and structure-activity studies of antiplatelet 2-morpholinochromones." Monash University, Dept. of Medicine, 2003. http://arrow.monash.edu.au/hdl/1959.1/7606.

Full text

APA, Harvard, Vancouver, ISO, and other styles

34

Tintoré, Gazulla Maria. "hAGT inhibitors as chemotherapy enhancers." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/299794.

Full text

Abstract:

The O6-alkylguanine DNA alkyltransferase (hAGT or MGMT) is a DNA repair protein in charge of removing alkyl adducts from the O6 position of guanines, blocking their cytotoxic effects and playing an important role as a resistance mechanism to chemotherapy in cancer patients. For these reasons, it is considered relevant as a prognosis marker of cancer and represents a potential therapeutic target. Intense research efforts have been devoted to the identification of small molecules capable of inhibiting hAGT activity and enhancing the cytotoxic effect of the alkylating agents in tumour cells. In this doctoral thesis, we have explored 10 compounds with potential inhibitory activity against hAGT. The analysis by mass spectrometry (ESI-MS) confirmed the complex formation of hAGT with 5 of them (compounds 5, 6, 7, 8 and 9). MTT cytotoxicity studies in cell culture showed that 2 compounds (5 and 8) were non-toxic and showed enhancement of carmustine toxicity. This compounds were further analysed by colony formation assays, which confirmed that compound 8 was non-toxic at long-term experiments and exhibited a stimulation effect of carmustine. Compound 8 seem to be the best candidates for hAGT inhibition, as it forms a complex with hAGT and it enhances BCNU without being toxic in MTT and colony formation assays. Due to the lack of a consistent in vitro assay for the activity of hAGT, we have devoted part of this doctoral thesis to the search of bio and nanotechnologies to detect hAGT activity which enable the evaluation of potential inhibitors of the protein. Chapter 2 describes the development of a new fluorescence method using the conformational change of a DNA Gquadruplex, the thrombin binding aptamer (TBA), as a molecular beacon for the detection of hAGT activity and the development of new inhibitor compounds. The conformational change of TBA is further explored to develop a detection platform on DNA origami which allows de quantification of the repair activity of hAGT on a single molecules basis, through the direct visualization by AFM of the interaction of TBA-thrombin when its G-quadruplex structure is restored. In addition, this work reports the synthesis of guanine derivatives modified at position 6 and properly functionalized for their incorporation into double stranded oligonucleotides that are used for the development of another novel fluorescence methodology to evaluate hAGT activity and to assess potential inhibitors as enhancers of chemotherapy. Finally, during a short stay in the University of Milan, we have developed a new sensor to detect a methylation in TBA using three types of nanoparticles: AuNPs, SPIONs and AuSPIONs. AuSPIONs combine the features of the gold coating and the magnetic core, and exhibit similar performance as AuNPs and SPIONs in UV, DLS and MRI assays to detect thrombin and a single methylation in TBA. Ths results provide the basis for the development of a new straightforward method to study hAGT activity and to evaluate potential inhibitors.
La proteïna de reparació de l’ADN alquilguanina-ADN-O6-alquiltransferasa (hAGT) elimina productes d'alquilació en la posició O6 de les guanines, bloquejant la citotoxicitat dels agents alquilants i produint resistència a la quimioteràpia. Es considera rellevant com a marcador de pronòstic en càncer i representa una potencial diana terapèutica. L’objectiu a llarg termini d’aquesta tesi doctoral és trobar inhibidors de l’activitat d’hAGT per millorar l'efecte de la quimioteràpia en pacients amb càncer. En primer lloc, es va avaluar la capacitat de 10 compostos, potencials inhibidors d’h!GT, de formar un complexe amb hAGT utilitzant espectrometria de masses, i es va estudiar la seva toxicitat en cultius cel·lulars a través d'assajos de MTT i de formació de colònies. A continuació, es desenvolupen diferents mètodes per a la detecció de l’activitat d’hAGT, per a avaluar els potencials inhibidors d’aquesta proteïna in vitro. Dos d’aquests mètodes utilitzen el canvi conformacional que es produeix en l’aptàmer d’unió a la trombina (TBA) en introduir una O6-metilguanina, substracte d’hAGT, en una de les seves tètrades centrals. En el primer mètode es va emprar el TBA per generar un sensor de fluorescència incorporant un fluoròfor i un inhibidor de fluorescència a cadascun dels seus extrems. Aquest sensor permet la detecció de la disminució en la fluorescència deguda al canvi conformacional del TBA produït per l’activitat d’hAGT. Posteriorment, el canvi conformacional del TBA va permetre dissenyar un biosensor de l'activitat d'hAGT a nivell unimolecular sobre la superficie d’un origami d'ADN. La interacció del TBA amb la seva proteïna diana, l’alfa-trombina, es va seguir per AFM per detectar que l’estructura de G-quàdruplex metilada es restableix per la reparació d’hAGT. El tercer mètode es basa en la transferència de fluorescència al centre actiu d’h!GT degut a la reparació d’un oligonucleòtid que conté una guanina modificada amb un grup alquil marcat amb un fluoròfor. Amb aquest objectiu, es va portar a terme la síntesi química d’aquesta guanina modificada. En el marc d’una estada en la Universitat de Milà, es descriu l’estudi de nanopartícules funcionalitzades amb TBAs per a detectar una metilació en una guanina utilitzant espectroscòpia d’UV, DLS o MRI, amb l’objectiu de desenvolupar un nou assaig de l’activitat reparadora d’ADN d’h!GT.

APA, Harvard, Vancouver, ISO, and other styles

35

Mendieta, Martínez Laura. "Protease inhibitors as therapeutic agents." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/279388.

Full text

Abstract:

Proteases are involved in a high number of diseases, and thus, are relevant targets. For that reason our main goal was the discovery of protease inhibitors as therapeutic agents. We focused our study in four proteases: dipeptidyl peptidase IV (diabetes mellitus type 2), prolyl oligopeptidase (cognitive disorders) and cathepsins L and B (cancer).For the discovery of inhibitors, three strategies were selected: medicinal plant screening, high throughput screening and the characterization of a combinatorial chemistry library. Once accomplished the DPP IV recombinant expression optimization, the protein was studied by means of nuclear magnetic resonance (NMR) in order to obtain information of its dynamism. Since DPP IV is a large protein, a strategy combining selective labeling and the use of TROSY-HSQC experiments was used. From the 14 methionine residues of the protease, 11 of them were detected in the NMR spectra. Then, a study of the inhibitor effect on the NMR spectra of DPP IV was done. Interestingly, the corresponding spectra of DPP IV / inactivator afforded an extra signal. We believe that it is a consequence of a small structural change that the protease suffers after inhibition. Afterwards, we planned to find DPP IV from botanical sources. First, we selected plants that were already reported to have antidiabetic action. Common antidiabetic plants were chosen, as well as Brazilian plants and others from the Traditional Chinese Medicine. Besides, a library of Mediterranean plants was also selected. After, extraction and testing of DPP IV inhibitory activity was done. From our tailored collection, the plant AP-3 was selected for further analysis. After fractionation and purification, two molecules were found to be DPP IV inhibitors. Kinetic experiments of the best one, AP-3-a, demonstrated that it was inhibiting DPP IV in a parabolic manner. Then, AP-3-a inhibition of DPP IV was analysed by NMR. The extra signal that was observed with competitive inhibitors was not present. We hypothesized that the lack of appearance of this signal is a result of the parabolic inhibition of AP-3-a. Then, we planned the identification of POP inhibitors by HTS. Our strategy was based in the use of libraries containing non-toxic compounds and lead-like properties. The assay we selected was FP, which allowed the identification of protein binders by competition with a fluorophore-labelled probe. First, the peptide probes were validated as useful probes for the FP assay. Then, the HTS was carried out. Over the 4,500 tested compounds, 73 hits were found to be POP binders. Later, 37 hits were selected by means of clustering, docking data and FP results in order to be validated as POP inhibitors. The subset of molecules was evaluated by enzymatic assays. Six compounds presenting the highest POP inhibition ration were selected for further study. Finally, two POP inhibitors have been described. HTS-43 is a competitive POP inhibitor and HTS-75 displays a parabolic behaviour. It was the first time that parabolic inhibition is reported for POP. We believe that the existence of a non-competitive site would help in the understanding of the relationship between POP and mental diseases. Finally, a novel peptidyl aryl vinyl sulfone library was tested for its inhibitory activity against cathepsins L and B. Among all the 20 molecules of the library, a potent covalent irreversible cathepsin L inhibitor has been found, PAVS-20. The progress-curve of the pre-incubation time representation allowed the calculation of its inhibition constants. Furthermore, evaluation of subsite preferences was done by docking analysis. This allowed understanding the experimental differences in inhibition constants obtained for similar compounds. Since cathepsins L and B are targets for cancer, molecules of the PAVS library are promising candidates for the development of new anticancer drugs.
Las proteasas están involucradas en un alto número de enfermedades y por lo tanto, son dianas terapéuticas relevantes. Por este motivo, nuestra principal meta era el descubrimiento de inhibidores de proteasas cómo agentes terapéuticos. Para ello nuestro estudio en cuatro proteasas: la dipeptidil peptidasa IV, la prolil oligopeptidasa y las catepsinas L y B. Para la búsqueda de inhibidores, se seleccionaron tres estrategias: cribado de plantas medicinales, cribado de alto rendimiento y caracterización de una biblioteca proveniente de la química combinatoria. Una vez se llevó a cabo la expresión recombinante de la DPPIV, la proteína se estudió mediante resonancia magnética nuclear (NMR) para obtener información acerca de su dinamismo. Dado que es una proteína grande, se utilizó una estrategia en la que se combinó el marcaje selectivo y el uso de experimentos TROSY-HSQC. Posteriormente, se realizó el estudio de la DPP IV en presencia de sus inhibidores, para observar como estos afectan a la estructura proteica. Después, se realizó la búsqueda de inhibidores de la DPP IV a partir de extractos de plantas medicinales. De nuestra colección, se seleccionó el extracto de la planta AP-3 para un análisis en profundidad. Se detectaron dos inhibidores de la proteasa. El más potente, AP-3-a, se caracterizó cómo un inhibidor parabólico. Después se llevó a cabo el estudio del complejo DPP IV/AP-3-a por NMR. En cuanto a la POP, se realizó la búsqueda de inhibidores mediante cribado de alto rendimiento (HTS). De los 4,500 compuestos testados se obtuvo un total de 73 hits en el ensayo de polarización de la fluorescencia (FP). La validación de estas moléculas mediante docking, clustering y ensayos enzimáticos, permitió identificar seis potentes inhibidores de POP. Uno de ellos, HTS-75, se caracterizó como un inhibidor parabólico. Esta es la primera vez que se describe un inactivador de este tipo para POP. Finalmente, en cuanto a las catepsinas L y B, se cribó una librería de peptidil aril vinil sulfonas. Entre las 20 moléculas testadas se encontró un potente inhibidor irreversible de la catepsina L, el PAVS-20. Además, se realizó un estudio de docking que permitió evaluar las preferencias de los subsitios de las dos proteasas.

APA, Harvard, Vancouver, ISO, and other styles

36

Aubert-Jürgens, Ana. "STAT3 inhibitors for cancer treatment." [S.l.] : [s.n.], 2005. http://elib.tu-darmstadt.de/diss/000563.

Full text

APA, Harvard, Vancouver, ISO, and other styles

37

Smith, David. "Fasciola hepatica Kunitz-type inhibitors." Thesis, Queen's University Belfast, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728662.

Full text

Abstract:

The aim of this thesis was to characterize Kunitz-type (KT) protease inhibitors expressed by the helminth parasite Fasciola hepatica during infection of the mammalian host. KT inhibitors have traditionally been considered serine protease inhibitors. A P1 residue, typically Lys or Arg, within a reactive loop, determines serine protease inhibition specificity. Recombinant KT inhibitor expression was carried out for the gene identified in F. hepatica (fhktl) that encodes an uncommon P1 Leu residue. Inhibition studies found that FhKT1 did not inhibit serine proteases, but did inhibit cysteine protease, particularly cathepsin L-like cysteine proteases. Molecular modelling predicted that residues P1 Leu15 to P4’ Arg19 of the KT inhibitor interact with the S2 and S2’ pockets of the cysteine protease. Interrogation of the F. hepatica draft genome identified seven KT inhibitors in this parasite, which were found to fall into 5 distinct groups. The fhktl group is made up of three highly similar KT genes, two with a P1 Leu residue (fh ktl.1 and fh k tl.2), but another with a P1 Arg (fh ktl.3). Recombinant FhKT1.3was found to inhibit cysteine proteases, as well as trypsin. Transcriptomic analysis revealed that the fhkt genes are temporally regulated across mammal-associated parasite life-cycle stages, with only the fhktl group expressed at all stages. The fhktl group was also found to be the most highly expressed, as well as the only FhKTs secreted by the parasite. Based on the inhibition specificity of FhKT1 inhibitors, their constituative expression, tissue-specific localization and their presence in parasite secretions, these inhibitors are proposed to be multi-functional, with a primary role in the regulation of F. hepatica and host cathepsin L- like cysteine proteases. Based on the ability of FhKT1.3 to inhibit trypsin, this inhibitor could also function in parasite defence. FhKT1 represents a target at which a novel drug or vaccine could be directed.

APA, Harvard, Vancouver, ISO, and other styles

38

Dou, Dengfeng. "Mammalian and viral protease inhibitors." Diss., Wichita State University, 2010. http://hdl.handle.net/10057/3281.

Full text

Abstract:

Chronic Obstructive Pulmonary Disease (COPD) is currently the fourth leading cause of death in the US. COPD is a multi-factorial disorder characterized by an oxidant/antioxidant imbalance, inflammation, a protease/antiprotease imbalance and apoptosis. This dissertation describes a general strategy for the design, synthesis and biochemical evaluation of dual function inhibitors which could potentially interrupt the above disorder, thereby enhancing the treatment of COPD. An example of this type inhibitor based on the 1,2,5-thiadiazolidin-3-one scaffold has been proven effective against both human neutrophil elastase (HNE) and caspase-1, two key enzymes responsible for elastin degradation and inflammation, respectively. In addition, an X-ray crystal structure and a high resolution mass spectrum of inhibitor bonded HNE have proven the proposed mechanism of HNE inactivation. Furhtermore, simple reversible competitive inhibitors of COPD-related enzymes (HNE and proteinase 3) have also been designed, synthesized and evaluated biochemically. West Nile virus and Dengue virus are recognized as a major health threat that affects millions of people worldwide. However, there is currently no treatment or vaccine available for the virus infection. This dissertation describes the design, synthesis and biochemical evaluation of reversible competitive inhibitors of both West Nile virus and Dengue virus NS2B-NS3 protease. Combinatorial chemistry and click chemistry methods have been used in the design of the protease inhibitor and the identified hit was optimized using computational programs (AutoDock4 and SYBYL). Several more hits were identified during the optimization and further development could potentially lead to very potent inhibitors of NS2B-NS3 protease with good pharmacokinetics and oral bioavailability.
Thesis (Ph.D.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry

APA, Harvard, Vancouver, ISO, and other styles

39

Tabor, Alethea Bernice. "Synthesis of GABA-T inhibitors." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305797.

Full text

APA, Harvard, Vancouver, ISO, and other styles

40

Lee, Victor. "Synthesis of HIV protease inhibitors." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291434.

Full text

APA, Harvard, Vancouver, ISO, and other styles

41

Namgoong, Sung Keon. "The synthesis of glycosidase inhibitors." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236199.

Full text

APA, Harvard, Vancouver, ISO, and other styles

42

Varley, Denise Joyce. "Novel inhibitors of glutamine synthase." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308650.

Full text

APA, Harvard, Vancouver, ISO, and other styles

43

Chen, Zhiqiang. "Identification of HIF-1 inhibitors." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503047.

Full text

APA, Harvard, Vancouver, ISO, and other styles

44

El, Moaty Ibrahim S. "Surfactant properties of corrosion inhibitors." Thesis, University of Hull, 2011. http://hydra.hull.ac.uk/resources/hull:5807.

Full text

Abstract:

Corrosion is one of the most common, costly and widespread industrial problems in the oil and gas production industry. Surfactant addition is one of many ways to inhibit the corrosion of metals, especially on hard-to-reach surfaces such as the inside of a pipe through which fluid is flowing. The application of small quantities of an inhibitor to production fluids is the most cost-effective method for imparting corrosion protection to a system. Despite the popularity of surfactants as corrosion inhibitors, their actual behaviour inside a pipeline is not well understood. The homologous alkylbenzyldimethylammonium chlorides CnBDMAC series is one of the most common corrosion inhibitors used in the oil industry. This thesis addresses some of the surfactant properties of these corrosion inhibitors which are not studied in detail (or often ignored) through electrochemical studies. Firstly, the adsorption behaviour of these corrosion inhibitors at the air-water interface was investigated as a function of the alkyl chain length, temperature and the concentration of the added electrolyte. The surfactant chain length and brine addition were found to have a great influence on the adsorption behaviour and hence on the critical micelle concentration (cmc). Secondly, the ability of CnBDMAC corrosion inhibitors to stabilize both oil-in-water and water-in-oil emulsions and the phase inversion of the emulsions as the inhibitor structure, temperature, electrolyte concentration and oil type change has been studied. The partitioning behaviour of C16BDMAC between an aqueous brine phase and an oil phase has been investigated as well as a function of electrolyte concentration. Studying the adsorption behaviour of surfactant corrosion inhibitors at solid-liquid interfaces provides important information about their action mechanism, which in turn helps in improving their efficiency. The adsorption behaviour of CnBDMAC molecules has been studied as a function of the surfactant chain length, temperature and electrolyte concentration using the Quartz Crystal Microbalance (QCM) technique. The QCM technique provides an effective, easy to setup and quick in-situ monitoring method for studying qualitatively the adsorption of surfactants at the solid-liquid interface. However, the determined adsorption isotherms were found to overestimate the amount of surfactant adsorbed. Therefore, the depletion method has been used to study the adsorption characteristics of CnBDMAC onto a stainless steel powder. Pipes used in oilfields for crude oil transportation are mainly made of mild steel. Accordingly, it is crucial to understand the adsorption behaviour of these corrosion inhibitors onto the mild steel surface. The effect of surfactant structure, temperature and electrolyte concentration on the adsorption behaviour of CnBDMAC onto mild steel particles using the depletion method has been investigated. In addition, the depletion method has been used to study the adsorption of CnBDMAC onto sand which is one of the main corrosion inhibitor consuming-solids encountered naturally in the oilfield. The adsorption studies performed revealed that these inhibitors have a strong affinity for sand particles, particularly at low temperatures and diluted inhibitor concentrations. Finally, the corrosion inhibition performance of hexadecylbenzyldimethylammonium chloride (C16BDMAC) corrosion inhibitor has been investigated through the linear polarisation resistance technique as a function of the added sand amount. A model has been proposed and applied successfully to determine the percentage decrease in the corrosion inhibition efficiency of C16BDMAC with changes in the amount of sand added.

APA, Harvard, Vancouver, ISO, and other styles

45

Horbert, Rebecca [Verfasser]. "Photoactivatable Kinase Inhibitors / Rebecca Horbert." Kiel : Universitätsbibliothek Kiel, 2015. http://d-nb.info/1079524029/34.

Full text

APA, Harvard, Vancouver, ISO, and other styles

46

Salako, Adetokunbo Adeniran. "Topoisomerase inhibitors based on podophyllotoxins." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337615.

Full text

APA, Harvard, Vancouver, ISO, and other styles

47

Colucci, Marie A. "Quinone based inhibitors of NQ01." Thesis, University of Nottingham, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.478964.

Full text

APA, Harvard, Vancouver, ISO, and other styles

48

Donlan, Andrew Michael. "Electrochemical sensing of enzyme inhibitors." Thesis, Cardiff University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316288.

Full text

APA, Harvard, Vancouver, ISO, and other styles

49

Slater, Martin John. "Phosphonamidate inhibitors of #beta#-lactamase." Thesis, University of Huddersfield, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260055.

Full text

APA, Harvard, Vancouver, ISO, and other styles

50

Anson, T. C. "Synthesis of potential enzyme inhibitors." Thesis, University of Exeter, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372033.

Full text

APA, Harvard, Vancouver, ISO, and other styles

Dissertations / Theses on the topic 'Inhibitors'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles