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Tesi sul tema "Cysteine protease inhibitor"

Autore: Grafiati
Pubblicato: 4 giugno 2021
Ultima modifica: 5 febbraio 2022

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1

Chen, Hongyuan. "Development of macrocyclic β-strand calpain cysteine protease inhibitors". Thesis, University of Canterbury. Chemistry, 2011. http://hdl.handle.net/10092/5582.

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The work in this thesis reports studies directed to developing a calpain cysteine protease inhibitor that could be of value in slowing cataract development in humans. The work focuses on the development of macrocyclic compounds which can have advantages over acyclic compounds due to their resistance to proteolytic hydrolysis, improved selectivity, bioavailability and membrane permeability. A review of X-ray crystal structures of natural and synthetic calpain inhibitors complexed with the cysteine protease calpain show the inhibitors generally bind in the enzyme active site in an extended β-strand conformation. The calpain inhibitor SJA-6017 has been identified as a suitable lead compound. The importance of the para-fluoro group in SJA-6017 has been investigated. Modifications have been made to constrain this basic structure within a macrocycle and restrict the peptide chain as a β-strand conformation. Macrocycle CAT811 is a potent calpain 1 and 2 inhibitor and shows promise in slowing the progression of cortical cataract in trials with sheep having a hereditary propensity towards the development of cataract. In this thesis I report studies directed to improve the yield of the key RCM macrocyclisation step in the synthesis of aldehyde CAT811 and of three ester analogues (2.1, 2.3 and 2.4). I also report the development of a more commercial route to CAT811 not involving RCM but using intramolecular nucleophilic cyclisation. This intramolecular nucleophilic cyclisation strategy was attempted for the preparation of a histidine containing macrocyclic ester (4.1a) but was unsuccessful. An alternate strategy involving intramolecular lactamization proved successful for the synthesis of histidine-based macrocyclic esters (4.1a-4.3a). Reduction to the corresponding alcohols (4.1b-4.3b) was successful and oxidation of (4.1b and 4.3b) afforded the corresponding aldehydes (4.1c and 4.3c) for biological assay against ovine calpain 2. Aldehyde 4.3c has an IC50 of 1 μM and the corresponding alcohol 4.3b shows no activity (IC50 > 50 μM) consistent with the modelling which indicated that these two compounds did not adopt a β-strand conformation in the docking studies. Aldehyde 4.1c, on the other hand, shows significant inhibitory activity with an IC50 of 238 nM but as expected the corresponding alcohol 4.1b shows little activity (IC50 = 29 μM). Modelling studies showed that both the aldehyde 4.1c and the alcohol 4.1b on docking can form a β-strand with appropriate H-bonding interactions. The aldehyde is more active than the alcohol due to the reactivity of the aldehyde warhead allowing for the reversible formation of a hemiacetal. A similar difference in reactivity is observed for CAT811 (30 nM) and its alcohol analogue (700 nM). These results demonstrate the value of molecular modelling as a screening mechanism before unproductive synthetic work is considered.
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2

Musonda, Chitalu Christopher. "Antimalarial and cysteine protease inhibitor pharmacophores as scaffolds for new antimalarial agents". Doctoral thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/11811.

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Includes bibliographical references.
The work in this thesis is threefold: (i) A new series of antiplasmodial agents were initially designed based on the β-amino alcohol bioactiphore, a subunit that is found in a number of antimalarial agents. (ii) Various thiosemicarbozones and semicarbozones were designed and synthesized as potential mechanism-based inhibiotrs of parasitic cysteine proteases. (iii) Multicomponenet reactions offer the advantage of introducing chemical diversity in fewer steps than conventional multi step organic synthesis. New chloroquine-type compounds were designed and synthesized using the Ugi 4 component condensation reaction and its variants. The synthesized compounds ranged from simple peptidic molecules to rigid heterocycles.
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3

Vindebro, Reine. "Studies on secreted cysteine proteases of Streptococcus pyogenes : IdeS and SpeB". Doctoral thesis, Umeå universitet, Institutionen för molekylärbiologi (Medicinska fakulteten), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-88223.

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The pathogen Streptococcus pyogenes is a significant cause of human morbidity and mortality. Most of the work in this thesis is focused on streptococcal virulence factor IdeS, but the thesis also features work on SpeB, another streptococcal virulence factor. Both IdeS and SpeB are secreted cysteine proteases and both have previously been shown to degrade human IgG. IgG is the only known substrate for IdeS while SpeB is a more promiscuous protease with a larger number of identified substrates. A significant part of the data presented in this thesis is the result of designing and optimizing methods to detect and accurately measure the proteolytic degradation of IgG. Methods aimed at measuring the binding interactions between enzyme and substrate have also been frequently utilized. I show that IdeS is a monomeric protease, as opposed to previously published data that suggested it to be dimeric. IdeS cleaves the two heavy chains of IgG in a two-step reaction and I demonstrate that the first cleavage is magnitudes faster than the second one. This means that IdeS is a more efficient enzyme than previously thought. The difference in rate cannot completely be explained by a loss of affinity between IdeS and IgG after the cleavage of the first heavy chain. The velocity of IdeS is further increased by the presence of human Cystatin C, via an unknown mechanism. Cystatin C is normally a protease inhibitor and it having an opposite effect is puzzling.The synthesis and evaluation of novel inhibitors are also described. Peptide analogues mimicking the sequence surrounding the scissile bond on IgG - with an amino acid replaced with a more rigid motif - act as specific, but low-affinity, inhibitors of IdeS. The peptide analogues’ inhibitory capacity for SpeB and papain was also assayed.When it comes to SpeB, I show that it does not have IgG as a substrate under physiological conditions, in contrast to what was previously thought. This thesis does not only present findings on the IgG degrading capacity of IdeS and SpeB but also include data on fundamental enzymatic properties for these proteases.
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4

James, Karen Amanda Ellis. "Design, synthesis, and evaluation of novel cysteine protease inhibitors". Diss., Georgia Institute of Technology, 2002. http://hdl.handle.net/1853/30283.

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5

Friedrich, Beate. "Cathepsine B, H, L und ihre Inhibitoren im Gewebe und in Zellkulturen der Prostata". Doctoral thesis, [S.l.] : [s.n.], 1999. http://deposit.ddb.de/cgi-bin/dokserv?idn=957675186.

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6

Pol, Ewa. "Mechanism of interaction of the mammalian cysteine protease inhibitors, cystatin A and B, with target proteases /". Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 2001. http://epsilon.slu.se/avh/2001/91-576-5927-3.pdf.

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7

Leung, Donmienne Doen Mun. "Studies of serine and cysteine protease inhibitors /". St. Lucia, Qld, 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16491.pdf.

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8

Ovat, Asli. "Design, synthesis and evaluation of cysteine protease inhibitors". Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/33822.

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Cysteine proteases are important drug targets due to their involvement in many biological processes such as protein turnover, digestion, blood coagulation, apoptosis, cell differentiation, cell signaling, and the immune response. In this thesis, we have reported the design, synthesis and evaluation of clan CA and clan CD cysteine protease inhibitors. Aza-peptidyl Michael acceptor and epoxide inhibitors for asparaginyl endopeptidases (legumains) from the bloodfluke, Schistosoma mansoni (SmAE) and the hard tick, Ixodes ricinus (IrAE) were designed and synthesized. SARs were similar, but with some notable exceptions. Both enzymes prefer disubstituted amides to monosubstituted amides in the P1' position and potency increased as we increased the hydrophobicity of the inhibitor in this position. Extending the inhibitor to P5 resulted in increased inhibitory potency, especially against IrAE, and both enzymes prefer small over large hydrophobic residues in the P2 position. Aza-peptide Michael acceptor inhibitors are more potent than aza-peptide epoxide inhibitors and, for some of these compounds, second order inhibition rate constants are the fastest yet discovered. We have also synthesized aza-peptidyl Michael acceptor and epoxide inhibitors for the parasitic cysteine proteases; cruzain, rhodesain. We have found that monosubstituted amides were favored over disubstituted amides indicating the involvement of the amide hydrogen in a H-bond network. We have shown that aza-peptide epoxides were as potent as Michael acceptors and we have obtained compounds with IC50 values as low as 20 nM. We have worked on the synthesis of heterocyclic peptidyl α-ketoamides, peptidyl ketones and aza-peptidyl ketones as calpain inhibitors. We have synthesized peptidyl α-ketoamides with nucleotide bases in the primed region to create compounds that can cross the blood-brain barrier. We have improved the potency by introducing a hydrophobic group on the adenine ring. We have obtained compounds with Ki values in the nanomolar range. We have designed peptidyl aminoketones as a new class of inhibitors for calpain. Peptidyl aminoketones were less potent than peptidyl α-ketoamides but still reasonable inhibitors of calpain that have the potential to cross the BBB.
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9

Mehrtens, (nee Nikkel) Janna Marie. "The Design, Synthesis and Biological Assay of Cysteine Protease Specific Inhibitors". Thesis, University of Canterbury. Chemistry, 2007. http://hdl.handle.net/10092/3271.

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This thesis investigates the design, synthesis and biological assay of cysteine protease inhibitors within the papain superfamily of cysteine proteases. This is achieved by examining the effect of inhibitor design, especially warheads, on IC₅₀ values and structureactivity relationships between cysteine protease inhibitors of the papain superfamily. The representative proteases used are m-calpain, μ-calpain, cathepsin B and papain. Chapter One is an introductory chapter; Chapters Two-Four describe the design and synthesis of cysteine protease inhibitors; Chapter Five discusses assay protocol; and Chapter Six contains the assay results and structure-activity relationships of the synthesised inhibitors. Chapter One introduces cysteine proteases of the papain family and examines the structure, physiology and role in disease of papain, cathepsin B, m-calpain and μ-calpain. The close structural homology that exists between these members of the papain superfamily is identified, as well characteristics unique to each protease. Covalent reversible, covalent irreversible and non-covalent warheads are defined. The generic inhibitor scaffold of address region, recognition and warhead, upon which the inhibitors synthesised in this thesis are based, is also introduced. Chapter Two introduces reversible cysteine protease inhibitors found in the literature and that little is known about the effect of inhibitor warhead on selectivity within the papain superfamily. Oxidation of the dipeptidyl alcohols 2.6, 2.26, 2.29, 2.30, 2.35 and 2.36 utilising the sulfur trioxide-pyridine complex gave the aldehydes 2.3, 2.27, 2.19, 2.2, 2.21 and 2.22. Semicarbazones 2.37-2.40 were synthesised by a condensation reaction between the alcohol 2.3 and four available semicarbazides. The amidoximes 2.48 and 2.49 separately underwent thermal intramolecular cyclodehydration to give the 3-methyl-1,2,4- oxadiazoles 2.41 and 2.50. The aldehydes 2.3 and 2.27 were reacted with potassium cyanide to give the cyanohydrins 2.51 and 2.52. The cyanohydrins 2.51 and 2.52 were separately reacted to give 1) the α-ketotetrazoles 2.43 and 2.55; 2) the α-ketooxazolines 2.42 and 2.58; 3) the esterified cyanohydrins 2.60 and 2.61. A two step SN2 displacement reaction of the alcohol 2.6 to give the azide 2.62, an example of a non-covalent cysteine protease inhibitor. Chapter Three introduces inhibitors with irreversible warheads. The well-known examples of epoxysuccinic acids 3.1 and 3.5 are discussed in detail, highlighting the lack of irreversible cysteine protease specific inhibitors. The aldehydes 2.3 and 2.27 were reacted under Wittig conditions to give the α,β-unsaturated carbonyls 3.14-3.18. Horner- Emmons-Wadsworth methodology was utilised for the synthesis of the vinyl sulfones 3.20- 3.23. The dipeptidyl acids 2.24 and 2.28 were separately reacted with diazomethane to give the diazoketones 3.25 and 3.26. The diazoketones 3.25 and 3.26 were separately reacted with hydrogen bromide in acetic acid (33%) to give the α-bromomethyl ketones 3.27 and 3.28, which were subsequently reduced to give the α-bromomethyl alcohols 3.29-3.32. Under basic conditions the α-bromomethyl alcohols 3.29-3.32 ring-closed to form the peptidyl epoxides 3.33-3.36. Chapter Four introduces the disadvantages of peptide-based inhibitors. A discussion is given on the benefits of constraining inhibitors into the extended bioactive conformation known as a β-strand. Ring closing metathesis is utilised in the synthesis of the macrocyclic aldehyde 4.4, macrocyclic semicarbazone 4.15, the macrocyclic cyanohydrin 4.16, the macrocyclic α-ketotetrazole 4.18 and the macrocyclic azide 4.19. Chapter Five introduces enzyme inhibition studies. The BODIPY-casein fluorogenic assay used for establishing inhibitor potency against m-calpain and μ-calpain is validated. Assay protocols are also established and validated for cathepsin B, papain, pepsin and α- chymotrypsin. A discussion of the effect of solvent on enzyme activity is also included as part of this study. Chapter Six presents the assay results for all the inhibitors synthesised throughout this thesis and an extensive structure-activity relationship study between inhibitors is included. The alcohols 2.26 and 2.30 are unprecedented examples of non-covalent, potent, cathepsin B inhibitors (IC₅₀ = 0.075 μM selectivity 80-fold and 1.1 μM, selectivity 18-fold). The macrocyclic semicarbazone 4.15 is an unprecedented example of a potent macrocyclic cysteine protease inhibitor (m-calpain: IC₅₀ = 0.16 μM, selectivity 8-fold). The cyanohydrin 2.51 contains an unprecedented cysteine protease warhead and is a potent and selective inhibitor of papain (IC₅₀ = 0.030 μM, selectivity 3-fold). The O-protected cyanohydrin 2.61 is a potent and selective inhibitor of pepsin (IC₅₀ = 1.6 μM, selectivity 1.5-fold). The top ten warheads for potent, selective cathepsin B inhibition are: carboxylic acid, methyl ester, diazoketone, esterified cyanohydrin, α-bromomethyl ketone, α,β- unsaturated aldehyde, vinyl sulfones, α-bromomethyl-C₃-S,R-alcohol, alcohol and α,β- unsaturated ethyl ester. The selectivity of these warheads was between 5- and 130-fold for cathepsin B. The best inhibitors for cathepsin B were the α-bromomethyl ketone 3.26 (IC₅₀ = 0.075 μM, selectivity 16-fold), the α,β-unsaturated aldehyde 3.18 (IC₅₀ = 0.13 μM, selectivity 13-fold) and the esterified cyanohydrin 3.59 (IC₅₀ = 0.35 μM, selectivity 22- fold). Chapter Seven outlines the experimental details and synthesis of the compounds prepared in this thesis.
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10

Bridges, Sylvia Shadinger. "Design, synthesis, and evaluation of cysteine protease inhibitors". Diss., Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/29738.

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Abstract (sommario):
Proteases are enzymes that cleave protein amide bonds. Proteases are involved in a myriad of biological processes and are considered good targets for drug design. The proteases described herein are cysteine proteases, which utilize a cysteine residue thiol to attack the amide carbonyl, leading to amide bond cleavage. Irreversible inhibitors of cysteine proteases react with the active site cysteine, forming a covalent bond and rendering the enzyme inactive. The first project involved the design and synthesis of aza-peptide epoxide inhibitors for calpain, a clan CA, ubiquitous, calcium-activated human enzyme involved in neurodegeneration. These inhibitors proved to be poor inactivators of calpain, demonstrating that the aza-peptide epoxide is a warhead specific to clan CD cysteine proteases (caspases, gingipains). Subsequently, a known epoxide inhibitor of calpain was optimized to create a more potent inhibitor. Several of these inhibitors were more potent than the parent, and all were demonstrated to inhibit calpain in a breast cancer cell line which was treated with paclitaxel to spike calpain activity. The second project involved the design and solid phase synthesis of aza-peptide Michael acceptor caspases inhibitors. The two goals of this project were to develop a solid phase method for synthesis of inhibitors that are tedious to synthesize in solution phase, and to use a variety of amino acid residues to determine the optimal interactions in the P3? position for various caspases. The synthesis was successful, and the optimal P3? residues were determined. The third project involved the kinetic evaluation of aza-peptide epoxide and Michael acceptor inhibitor designed for the gingipains. Gingipains K and R are virulence factors in the pathology of Porphyromonas gingivalis involved in gingivitis and periodontal disease. These inhibitors proved to be extremely potent inactivators of gingipains, with some of the highest rates of inhibition measured in the Powers laboratory. Gingipain K preferred larger, aromatic moieties in the P1? position, while gingipain R preferred the Michael acceptor inhibitors, with the P1? substituent having less of an impact on potency.
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11

Campbell, Amy. "Design, synthesis, and evaluation of cysteine protease inhibitors". Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-11222005-132114/.

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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006.
Murthy, Niren, Committee Member ; Doyle, Donald, Committee Member ; Fahrni, Christoph, Committee Member ; May, Sheldon, Committee Member ; Powers, James, Committee Chair.
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12

Håkansson, Katarina. "Cystatin C functions in vitro and in vivo studies on target enzyme inhibition by cystatin C variants and cystatin C deficient mice /". Lund : Dept. of Clinical Chemistry, University of Lund, University Hospital, 1998. http://catalog.hathitrust.org/api/volumes/oclc/40343026.html.

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13

Rukamp, Karrie Eileen Adlington. "Design and synthesis of inhibitors for serine and cysteine proteases". Diss., Available online, Georgia Institute of Technology, 2004:, 2003. http://etd.gatech.edu/theses/available/etd-04082004-180343/unrestricted/rukamp%5Fkarrie%5Fe%5Fa%5F200312%5Fphd.pdf.

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14

Rukamp, Brian John. "Design, synthesis, and evaluation of novel thiobenzyl ester substrates and aza-peptide inhibitors for serine and cysteine proteases". Diss., Available online, Georgia Institute of Technology, 2004:, 2003. http://etd.gatech.edu/theses/available/etd-04072004-180202/unrestricted/rukamp%5Fbrian%5Fj%5F200312%5Fphd.pdf.

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15

Krauser, Joel Anderson. "Design, synthesis and evaluation of novel inhibitors and fluorogenic substrates for cysteine proteases and metallo proteases". Diss., Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/30003.

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16

Tehrani, Kamin A. "Synthesis and kinetics of cysteine proteinase inhibitors". Thesis, Georgia Institute of Technology, 1991. http://hdl.handle.net/1853/26967.

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17

Schönemeyer, Annett. "Charakterisierung der immunmodulierenden Wirkung eines Cysteinproteasen-Inhibitors der humanpathogenen Filarie Onchocerca volvulus". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2000. http://dx.doi.org/10.18452/14594.

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Filarien persistieren bis zu 15 Jahren in ihren Wirten. Als eine Ursache dieser Persistenz diskutiert man die Fähigkeit der Filarien, die Immunantwort des Wirtes gezielt zu modulieren und eine zelluläre Hyporeaktivität zu induzieren. In der vorliegenden Arbeit wurde untersucht, ob ein sezernierter Cysteinproteasen-Inhibitor (Onchocystatin) der humanpathogenen Filarie Onchocerca volvulus immunmodulierende Eigenschaften besitzt und an der Herausbildung eines hyporeaktiven Immunstatus des Wirtes beteiligt ist. Für die Untersuchungen wurde Onchocystatin als full length Molekül (rOv17) und als verkürztes Molekül (trOv17) rekombinant hergestellt. Das verkürzte trOv17 besitzt aufgrund des Fehlens des N-terminalen Bereiches eine verminderte proteaseinhibitorische Aktivität. Die in vitro Studien mit den rekombinant hergestellten O. volvulus Cystatinen verdeutlichen, daß rOv17 und auch trOv17 potente Immunmodulatoren sind, die sowohl die antigenspezifische als auch die polyklonal-stimulierte Proliferation von humanen PBMC inhibieren. Die zelluläre Hyporeaktivität ist dabei auf die Modulation von Monozytenfunktionen zurückzuführen. rOv17 und trOv17 modulieren die Antigenpräsentation, die Zytokinproduktion und die Expression kostimulatorischer Signale von humanen Monozyten. So konnte gezeigt werden, daß rOv17 und trOv17 die Aktivität von humanem Cathepsin L und S inhibieren und die Expression von HLA-DR, CD40 und CD86 vermindern. Die Modulation der Zytokinproduktion durch rOv17 und trOv17 ist durch eine verstärkte TNF-alpha und IL-10 Produktion und durch eine verminderte IL-12 Produktion charakterisiert. Desweiteren konnte in Neutralisationsstudien mit anti-IL-10 Ak gezeigt werden, daß die verminderte Expression von HLA-DR, CD40 und CD86 Folge der durch rOv17 und trOv17 induzierten verstärkten IL-10 Produktion ist. Im Gegensatz dazu bleibt die verminderte IL-12 Produktion und die verminderte polyklonal-stimulierte Proliferation humaner PBMC auch nach der Neutralisation von IL-10 bestehen. Die Studien mit den rekombinant hergestellten O. volvulus Cystatinen zeigen, daß rOv17 und trOv17 ihr immunologisches Umfeld auf vielfältige Art und Weise modulieren. Dabei spielt vermutlich die Inhibition der Aktivität einer Wirtscysteinprotease, aber auch ein von der Funktion als Cysteinproteasen-Inhibitor unabhängiger Mechanismus eine Rolle. Der Cysteinproteasen-Inhibitor der Filarie O. volvulus besitzt somit die Eigenschaft, die Immunantwort des Wirtes zu modifizieren, und ist vermutlich eine wesentliche Komponente, die dem Parasiten eine lange Persistenz im Wirt ermöglicht.
Immune responses of individuals infected with filarial nematodes are characterized by a marked cellular hyporesponsiveness. The establishment of this hyporesponsiveness is considered as an important mechanism to avoid host immune responses which could eliminate the parasites. The present study is investigating the immunomodulatory potential of a 17 kD secreted cysteine protease inhibitor (onchocystatin) of the human pathogenic filaria Onchocerca volvulus. In vitro studies using recombinant onchocystatin (rOv17) identified this inhibitor as a potent immunomodulator. rOv17 suppresses the antigen-driven and the polyclonally-stimulated proliferation of human PBMC. This cellular hyporeactivity is due to the modulation of monocytic function by rOv17, comprising the modulation of antigenpresentation, the expression of costimulatory molecules and the production of cytokines. Thus rOv17 strongly inhibits the activity of human cathepsin L and S and reduces the expression of MHC class II molecules as well as the expression of CD40 and CD86 on human monocytes. The modulation of cytokine production by rOv17 is characterized by an initial increase of TNF-alpha which is followed by an increase of IL-10 and a decrease of IL-12. By neutralization studies it was shown that the suppression of MHC class II molecules and of CD86 and CD40 is mediated by the rOv17 induced increase of IL-10. In contrast cellular hyporeactivity and the reduced IL-12 production remain unaffected by neutralization of IL-10. In comparison to rOv17 a truncated onchocystatin (trOv17) with lowered protease inhibitory activity was investigated. Surprisingly even trOv17 is immunomodulatory active suggesting that immunomodulation by onchocystatin is mediated by both an inhibitor-dependent and an inhibitor-independent mechanism. These data demonstrate that onchocystatin is a potent immunomodulator of host immune responses and in consequence is an essential component that enables the parasites a long persistence within their hosts.
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18

Rapolu, Chaitanya. "Inhibition of Cysteine Protease by Platinum (II) Diamine Complexes". TopSCHOLAR®, 2011. http://digitalcommons.wku.edu/theses/1137.

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Chemotherapy is the first line of treatment used in cancer. Chemotherapy drugs such as cisplatin, carboplatin and oxaliplatin are used in treatment. Cisplatin enters the cell through copper transporter CTR1 by passive diffusion and bind to DNA and proteins. Cisplatin is found to inhibit several enzymes targeting cysteine, histidine and methionine residues, which are expected to be responsible for its anticancer activity. A better understanding of how the size and shape and leaving ligands of platinum complexes affect cysteine protease, papain enzyme are studied. This could give new ways to optimize anticancer activity. The activity of papain enzyme was measured on UV-Visible spectroscopy. The inhibition profile of papain with different platinum (II) complexes, and with different combinations was studied.
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19

Faucher, Ryan Michael John. "CHARACTERIZATION OF PHYTOCYSTATIN-LIKE CYSTEINE PROTEASE INHIBITORS OF TRICHOMONAS VAGINALIS". Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/2970.

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Trichomoniasis is a common STD caused by the parasitic protozoan Trichomonas vaginalis. The parasite is estimated to have infected roughly 3.7 million Americans. Complications from trichomoniasis can lead to cervical cancer in women and prostate cancer in men. One of the mechanisms of the parasite employs is using cysteine proteases to break down the cellular matrix of its host. However, three endogenous phytocystatin-like protease inhibitors have been found within the parasite’s genome. By recombinantly expressing these cystatins we have been able to test their ability to inhibit cysteine proteases such as papain and those found in T. vaginalis to find their effectiveness. By characterizing these inhibitors, it appears that they are effective at reducing the ability of T. vaginalis cysteine proteases and thus could be useful against the pathogenicity of the parasite.
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20

Koot, Gretchen E. "Serine and cysteine protease inhibitors for blockade of cell mediated cytotoxicity /". abstract and full text PDF (UNR users only), 2002. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3121138.

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21

Schulz, Franziska. "Synthese und Testung von Aziridin-2-Carboxylaten als Cystein-Protease-Inhibitoren". Doctoral thesis, [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=982199619.

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22

Dotse, Anthony Kwabla. "Design, synthesis and evaluation of novel inhibitors of cysteine proteases, metalloproteases and the proteasome, a unique high molecular weight proteolytic enzyme". Diss., Georgia Institute of Technology, 1997. http://hdl.handle.net/1853/29979.

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23

Gotz, Marion Gabriele. "Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases". Diss., Georgia Institute of Technology, 2004. http://hdl.handle.net/1853/8072.

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Cysteine proteases are a class of proteolytic enzymes, which are involved in a series of metabolic and catabolic processes, such as protein turnover, digestion, blood coagulation, apoptosis, fertilization and cell differentiation, and the immune response system. The development of novel potent and selective inhibitors for cysteine proteases has therefore gained increasing attention among medicinal chemists. In this thesis we have reported the design, synthesis, and evaluation of several peptidyl inhibitors for clan CA and clan CD cysteine proteases. We have continued the investigation of dipeptidyl vinyl sulfones as potent and selective inhibitors for dipeptidyl peptidase I (DPPI), a lysosomal cysteine protease, which is involved in the processing of intracellular proteases, such as granzymes. We have found that DPPI tolerates negatively charged amino acid residues in the P2 position with inhibition rates of 7,600 M-1s-1. Dipeptidyl vinyl sulfones with positively charged amino acid residues at the P1 position, however, do not inhibit DPPI at all. A second project focused on the epoxidation of the double bond of the vinyl sulfone moiety of the dipeptidyl vinyl sulfones. Instead of epoxidizing the double bond, we found that an isomerization had occurred. The newly formed compounds were determined to be allyl sulfones. We tested this new class of inhibitors with clan CA proteases and obtained inhibition rates of 560 M-1s-1 for Cbz-Leu-Phe-AS-Ph with calpain I. Two new classes of compounds for the clan CD protease S. mansoni legumain were designed, synthesized, and evaluated. Aza-peptidyl epoxides were found to be potent and selective inhibitors of S. mansoni legumain with IC50’s as low as 45 nM. Aza-peptide Michael acceptors were derived from the aza-peptide epoxide design and synthesized in an analogous fashion. The aza-peptide Michael acceptors inhibited S. mansoni legumain with even lower IC50’s, as low as 10 nM. However, the aza-peptide Michael acceptors react with thioalkylating agents contained in the buffer, such as DTT. The rates of degradation were determined spectroscopically, and half-lives of 3 to 20 minutes were measured. This observation gave us insights into the enzymatic mechanism and allowed us to determine the point of attack for the legumain active site cysteine thiol.
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24

Gheura, Iuliana L. "Design, synthesis and evaluation of AZA-peptide epoxides as inhibitors of cysteine proteases". Diss., Georgia Institute of Technology, 2002. http://hdl.handle.net/1853/30571.

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25

Götz, Marion Gabriele. "Design, synthesis, and evaluation of irreversible peptidyl inhibitors for clan CA and clan CD cysteine proteases". Available online, Georgia Institute of Technology, 2004, 2004. http://etd.gatech.edu/theses/available/etd-01282004-095929/unrestricted/Gotz%5FMarionG%5F200405%5Fphd2.pdf.

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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2004.
Dr. Suzanne Shuker, Committee Member ; Dr. Niren Murthy, Committee Member ; Dr. Donald Doyle, Committee Member ; Dr. Nicholas Hud, Committee Member ; Dr. James C. Powers, Committee Chair. Includes bibliographical references.
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26

Kroon, Matthys Christoffel. "High-throughput modelling and structural investigation of cysteine protease complexes with protein inhibitors". Thesis, Rhodes University, 2013. http://hdl.handle.net/10962/d1001619.

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The papain-like cysteine protease family (C1 proteases) is highly important because of its involvement in research and industrial applications and its role in various human diseases. Protein inhibitors are an important aspect of C1 protease biology and are relevant to its clinical, industrial and research importance. To study the interaction between the proteases and the inhibitors it is very useful to have accurate structural models of the protease-inhibitor complexes. To this end, a high-throughput pipeline for modelling complexes of papain-like cysteine proteases and protein inhibitors was implemented and tested (Tastan Bishop & Kroon, 2011). The pipeline utilizes a novel technique for obtaining modelling templates by using superpositioning to combine coordinates from separate experimental structures. To test the pipeline, models of complexes with known structures (test set) were modelled using many different templates and the resultant models evaluated to compare the quality of the different templates. It was found that use of the new technique to obtain templates did not introduce significant errors, while allowing closer homologs to be used for modelling - leading to more accurate models. The test set models were also used to evaluate certain steps of the modelling protocol. The effect of Rosetta energy minimization on model accuracy and the use of Rosetta energy and DOPE Z-score values to identify accurate models were investigated. Several complexes were then modelled using the best available templates according to criteria informed by the previous results. A website was built that allows a user to download any of the metrics or models produced in the study. This website is accessible at http://rubi.ru.ac.za/cpmdb
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27

Estrada, Sergio. "Cystatin A, a mammalian cysteine proteinase inhibitor : mechanism of inhibition of target proteinases by recombinant cystatin A variants /". Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1998. http://epsilon.slu.se/avh/1998/91-576-5448-4.gif.

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28

Ellis, Danielle René. "Characterization of a citrus vascular-specific zinc-binding cysteine proteinase inhibitor". Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/298754.

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A 712 bp partial cDNA clone (czbp- 1) of the citrus vascular zinc binding protein (CVZBP) was isolated using reverse transcriptase polymerase chain reaction (RT-PCR). The deduced amino acid sequence of czbp-1 was identical to the N-terminal amino acid sequence for the CVZBP. Czbp- 1 had a 549 bp open reading frame and two putative polyadenylation sites, +20 bp and +103 bp relative to the poly-A tail. The deduced amino acid sequence had identity with members of the Kunitz soybean proteinase inhibitor (KSPI) family. Many members of this family are present in high concentrations in storage organs such as seeds and tubers, increase in response to abiotic stress, and are considered defense or stress response proteins. The CVZBP did not appear to fit in this category. Unlike many members of the KSPI family CVZBP was not detected in citrus seeds and protein levels decreased in response to wounding. Transcript also decreased in response to osmotic stress; a similar result previously was reported for CVZBP protein levels. Accumulation of CVZBP and its transcript increased in Zn deficient citrus seedlings compared to those receiving sufficient levels of Zn, indicating that Zn nutrition can modulate CVZBP expression. Recombinant CVZBP was produced and used to determine the capacity of this protein to inhibit several types of proteinases. The CVZBP inhibited the cysteine proteinase, papain, but not the serine proteinases, trypsin and chymotrypsin. CVZBP protein was immunolocalized primarily to the xylem parenchyma in vascular tissue of citrus midribs. Based on these results it is possible that the CVZBP has a function in vascular differentiation. Cysteine proteinases were identified in developing tracheary elements in Zinnia cell cultures. Addition of inhibitors of cysteine proteinase to these cultures prior to secondary cell wall deposition prevents differentiation of the cells into tracheary elements. Perhaps cysteine proteinase inhibitors, such as the CVZBP, in the xylem, contribute to timing of tracheary element differentiation and determination.
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29

Turk, Boris. "Papain-like cysteine proteinases : regulation by proteinase inhibitors and pH /". Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1996. http://epsilon.slu.se/avh/1996/91-576-5227-9.gif.

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30

Arispe, Angulo Wara Milenka Trawick Mary Lynn. "Inhibitors of human cathepsin L and cruzain as therapeutic agents". Waco, Tex. : Baylor University, 2008. http://hdl.handle.net/2104/5290.

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31

Groves, Matthew Robert. "Crystallographic comparisons of the mode of inhibition of aspartic and cysteine proteases by synthetic inhibitors and their respective proregions". Thesis, Birkbeck (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265806.

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32

Musyoka, Thommas Mutemi. "Combined in silico approaches towards the identification of novel malarial cysteine protease inhibitors". Thesis, Rhodes University, 2017. http://hdl.handle.net/10962/4488.

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Malaria an infectious disease caused by a group of parasitic organisms of the Plasmodium genus remains a severe public health problem in Africa, South America and parts of Asia. The leading causes for the persistence of malaria are the emergence of drug resistance to common antimalarial drugs, lack of effective vaccines and the inadequate control of mosquito vectors. Worryingly, accumulating evidence shows that the parasite has developed resistant to the current first-line treatment based on artemisinin. Hence, the identification and characterization of novel drug targets and drugs with unique mode of action remains an urgent priority. The successful sequencing and assembly of genomes from several Plasmodium species has opened an opportune window for the identification of new drug targets. Cysteine proteases are one of the major drug targets to be identified so far. The use of cysteine protease inhibitors coupled with gene manipulation studies has defined specific and putative roles of cysteine proteases which include hemoglobin degradation, erythrocyte rupture, immune evasion and erythrocyte invasion, steps which are central for the completion of the Plasmodium parasite life cycle. In an aim to discover potential novel antimalarials, this thesis focussed on falcipains (FPs), a group of four papain-like cysteine proteases from Plasmodium falciparum. Two of these enzymes, FP-2 and FP-3 are the major hemoglobinases and have been validated as drug targets. For the successful elimination of malaria, drugs must be safe and target both human and wild Plasmodium infective forms. Thus, an incipient aim was to identify protein homologs of these two proteases from other Plasmodium species and the host (human). From BLASTP analysis, up to 16 FP-2 and FP-3 homologs were identified (13 plasmodial proteases and 3 human cathepsins). Using in silico characterization approaches, the intra and inter group sequence, structural, phylogenetic and physicochemical differences were determined. To extend previous work (MSc student) involving docking studies on the identified proteins using known FP-2 and FP-3 inhibitors, a South African natural compound and its ZINC analogs, molecular dynamics and binding free energy studies were performed to determine the stabilities and quantification of the strength of interactions between the different protein-ligand complexes. From the results, key structural elements that regulate the binding and selectivity of non-peptidic compounds onto the different proteins were deciphered. Interaction fingerprints and energy decomposition analysis identified key residues and energetic terms that are central for effective ligand binding. This research presents novel insight essential for the structure-based molecular drug design of more potent antimalarial drugs.
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33

Ntuli, Nelson Axe. "New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold". Master's thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/6352.

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Includes bibliographical references (leaves 120-125).
Many antimalarial drugs including chloroquine are no longer effective against the disease, as their efficacy has been decreased by the spread of drug resistant strains. This loss has been a major barrier to the effective treatment of malaria and has necessitated an urgent need to discover new antimalarial drugs. New 4-aminoquinoline isatin derivatives have been designed and synthesised. Isatin was used as a biologically validated starting point for the design of chemical libraries directed at the intended target due to its privileged nature. Included in the design of these isatin derivatives is the thiosemicarbazone moiety previously demonstrated to inhibit cysteine proteases from mUltiple protozoan parasites. Synthesized compounds were tested against the enzyme falcipain-2 (Rec-FP-2) as well as the parasite source of this protease, Plasmodium Jalciparum (P.f. W2). The results of structure activity relationship studies demonstrate the influence of substituents at position 5 of the isatin scaffold. With respect to the chain length, a two carbon methylene spacer between the aminoquinoline and isatin moieties, was found optimum. A 5-bromo isatin derivative with this spacer, compound 79b, was found to be the most active with an IC₅₀ value of 163.5 nM against the W2 parasite strain and second most active against the enzyme (lC₅₀ = 3.65 μM).
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34

Meighan, Mark A. "Putative strategies for the generation of antibodies and inhibitors of Cathespin S". Thesis, Queen's University Belfast, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263501.

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35

Njuguna, Joyce Njoki. "Structural analysis of prodomain inhibition of cysteine proteases in plasmodium species". Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1004081.

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Plasmodium is a genus of parasites causing malaria, a virulent protozoan infection in humans resulting in over a million deaths annually. Treatment of malaria is increasingly limited by parasite resistance to available drugs. Hence, there is a need to identify new drug targets and authenticate antimalarial compounds that act on these targets. A relatively new therapeutic approach targets proteolytic enzymes responsible for parasite‟s invasion, rupture and hemoglobin degradation at the erythrocytic stage of infection. Cysteine proteases (CPs) are essential for these crucial roles in the intraerythrocytic parasite. CPs are a diverse group of enzymes subdivided into clans and further subdivided into families. Our interest is in Clan CA, papain family C1 proteases, whose members play numerous roles in human and parasitic metabolism. These proteases are produced as zymogens having an N-terminal extension known as the prodomain which regulates the protease activity by selectively inhibiting its active site, preventing substrate access. A Clan CA protease Falcipain-2 (FP-2) of Plasmodium falciparum is a validated drug target but little is known of its orthologs in other malarial Plasmodium species. This study uses various structural bioinformatics approaches to characterise the prodomain‟s regulatory effect in FP-2 and its orthologs in Plasmodium species (P. vivax, P. berghei, P. knowlesi, P. ovale, P. chabaudi and P. yoelii). This was in an effort to discover short peptides with essential residues to mimic the prodomain‟s inhibition of these proteases, as potential peptidomimetic therapeutic agents. Residues in the prodomain region that spans over the active site are most likely to interact with the subsite residues inhibiting the protease. Sequence analysis revealed conservation of residues in this region of Plasmodium proteases that differed significantly in human proteases. Further prediction of the 3D structure of these proteases by homology modelling allowed visualisation of these interactions revealing differences between parasite and human proteases which will lead to significant contribution in structure based malarial inhibitor design.
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36

Chiyanzu, Idan. "Synthesis and biological evaluation of antiparasitic Cysteine protease inhibitors based on the Isatin Scaffold". Master's thesis, University of Cape Town, 2004. http://hdl.handle.net/11427/6300.

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Includes bibliographical references.
Widespread drug resistance, loss of efficacy and toxicity has limited the full utilization of the current available drugs against malaria and other parasitic diseases. This necessitates the development of new drugs. Meanwhile, the cysteine protease family of enzymes has been identified as potential targets for new modes of chemotherapy due to the numerous critical roles they play in the disease-causing agents. In this project, a non-peptidic and low molecular weight isatin (indole-2, 3-dione) possessing a wide range of pharmacological properties was used as a scaffold to which different moeities were appended. Potential inhibitors of parasitic cysteine proteases and three strains of P. falciparum were identified from synthesized libraries of compounds. Various N-substituted isatin derivatives were synthesized by KF/Ah03-mediated reaction of isatins with an alkyl, acyl or sulfonyl halide. A series of isatin-3-thiosemicarbazones were prepared by condensation of isatin I substituted isatins with thiosemicarbazide, and also a series of isatin-based Schiff and Mannich bases were prepared by reacting selected isatin-3-thiosemicarbazones with formaldehyde and appropriate secondary amines. To compare the effects of replacing the Mannich bases, a similar series of aminoquinolineethylene isatin-based derivatives were then synthesized. The synthesis was accomplished by condensation of quinoline-ethylene ketone forms with thiosemicarbazide. All synthesized compound were obtained in reasonable to excellent yields and characterized by spectroscopic and analytical techniques.
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37

Arafet, Cruz Kemel. "Computational Studies of the Mechanism of Catalysis and Inhibition of Cysteine Proteases". Doctoral thesis, Universitat Jaume I, 2017. http://hdl.handle.net/10803/436898.

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Falcipain-2 and cruzain are cysteine proteases involve in Malaria and Chagas disease. Today, many aspects of both, inhibition mechanism and catalytic mechanism of these enzymes are unclear. Thus, it is crucial to improve our understanding of how these enzymes work at molecular level for the design of new inhibitors. In the present Doctoral Thesis, different enzymatic mechanisms of the reaction catalyzed by cruzain, as well as several inhibition processes of cruzain and FP2, have been studied. Hybrid Quantum Mechanics/Molecular Mechanical potentials have been employed to run Molecular Dynamics simulations that allow obtaining the Free Energy Surfaces in terms of Potential of Mean Force. These calculations have allowed obtaining a complete picture of the reaction mechanisms, and the interactions between the inhibitor and the protein. Our results could be used for a rational design of new inhibitors with application in the treatment of severe human diseases.
La cruzaína y la falcipaína-2 están involucradas en muchas enfermedades. Tanto del mecanismo de inhibición como el mecanismo catalítico de estas enzimas son una incógnita. Mejorar la comprensión de estos sistemas enzimáticos a nivel molecular es crucial para el diseño de nuevos inhibidores. En la presente Tesis Doctoral se han estudiado diferentes mecanismos de la reacción catalizada por la cruzaína así como diversos procesos de inhibición de la cruzaína y la falcipaína-2. Se han empleado potenciales Mecánica Cuántica/Mecánica Molecular para realizar simulaciones de dinámica molecular y obtener las superficies de energía libre en términos de potenciales de fuerza media. Estos cálculos han permitido obtener un panorama completo del mecanismo de reacción, y de las interacciones entre el inhibidor y la proteína. Nuestros resultados han contribuido a nuestra comprensión de estos procesos, lo cual podría ser utilizado para un diseño racional de inhibidores con aplicación en el tratamiento de estas enfermedades.
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38

Wright, Michael Eugene. "Development, characterization, and use of a novel yeast expression system to identify inhibitors of the caspase-3 cell death protease /". Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/5018.

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39

Fey, Philipp [Verfasser]. "Neue wasserlösliche Cystein-Protease-Inhibitoren mit Aziridin-2,3-dicarbonsäure-Baustein / Philipp Fey". Mainz : Universitätsbibliothek Mainz, 2015. http://d-nb.info/1071745891/34.

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40

Latorre, Martínez Antonio. "Studies of sulfurated compounds and epoxidation of MDH adducts. New inhibitors of cysteine proteases". Doctoral thesis, Universitat Jaume I, 2015. http://hdl.handle.net/10803/669020.

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A. L. Martínez presents a PhD thesis on syntheses design and testing of new protease inhibitors targeting proteasome and cysteine proteases, e.g. cathepsins. With the various chapters his thesis covers fields from organic chemistry and medicinal chemistry, it includes detailed mechanistic studies on reaction mech- anisms and stereochemical output of the reactions. In chapter 1 A. L. Martínez presents his work on syntheses of unsaturated compounds from sulfinyl esters by elimination reaction. His detailed and very systematic studies resulted in a proposal for a complete reaction pathway which explains the formation of all by-products. He could also demonstrate by trapping reactions and mass spectrometric studies that the elimination of 2-arylsulfinyl esters proceeds via an intermolecular radical process. Chapter 2 describes the results on stereoisomerization studies of ¿-hydroxy-ß-sulfenyl-¿,ß-naphthoquinones. This isomerization is a consequence of sulfur-oxygen (S-O)-interactions which is proven by a systematic work including the X-ray structure of a representative compound, analyses of the isomerization with different bases and studies with model compounds which contain oxygen instead of sulfur. With this part he could demonstrate that the S-O-interaction is the driving reason for the stereochemical outcome of the isomerization reaction of the naphthoquinones. Chapter 3 also deals with stereoselectivity of an organic reaction, namely the epoxidation of 3-hydroxy-2-methylene esters. A. L. Martínez performed an extensive synthetic work for the optimization of the synthesis of differently substituted unsaturated esters by Morita-Baylis-Hillman (MBH) reaction and the optimization of their epoxidation. He confirmed the stereoselectivity and relative configuration by transformation of epoxides into the respective cyclic carbonates and their analyses by NOE mesurements. Chapter 4 covers a medicinal chemistry topic, the development of inhibitors of proteasome and cysteine proteases. The main goal of this part was the evaluation of new electrophilic warheads for peptidic or peptidomimetic inhibitors, i.e. warheads which covalently block the active site residues of the proteases. A. L. Martínez synthesized nitroalkenes which should covalently but reversibly inhibit the proteases. From these inhibitors also epoxides, cyclopropanes and aziridines should be derived. Furthermore, epoxy sulfones related to the well-known vinyl sulfone K11777 should be synthesized, as well as chloroketone sulfones, chlorovinyl sulfones, and finally carbonyl acetylenic inhibitors. A. L. Martínez not only succeeded in syntheses of all desired compounds (except the aziridines which only could be obtained as crude mixtures), but he also could improve the synthetic route for epoxy esters, and could confirm the stereochemistry of the epoxy sulfones by converting them into oxazolidinones and by NOE measurements. The biological testing proved the new warheads as suitable traps for proteases.
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Olsson, Sigrid-Lisa. "Characterisation of two endogenous mammalian cysteine proteinase inhibitors, bovine cystatin C and human cystatin A /". Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1999. http://epsilon.slu.se/avh/1999/91-576-5423-9.pdf.

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42

Sebesho, Biopelo Felicity. "Investigation of the efficacy of identified acetolactate synthase inhibitors, peptidyl cysteine protease inhibitors, thiolactomycins, and thiosemicarbazone compounds against Mycobacterium tuberculosis". Master's thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/3116.

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Abstract (sommario):
Includes bibliographical references (leaves 131-141).
Tuberculosis remains an important public health problem worldwide. There has been increase in the development of drug resistance towards INH and RIF, two of the frontline antimycobacterial drugs currently used in therapeutic regimes. As an attempt to address drug resistance, the World Health Organization has implemented the DOTS strategy in 182 countries. Moreover, new chemical libraries of potential antituberculosis drugs have been designed and synthesised. We therefore assessed 121 derivatives from the acetolactate synthase inhibitors, cysteine protease inhibitors, thiosemicarbazones, and thiolactomycins classes of compounds for in vitro efficacy against M. tuberculosis using the resazurin microtitre plate assay afterwhich active compounds were assessed for cytotoxicity in vitro against elicited peritoneal macrophages using the MTT assay. Of the 38 acetolactate synthase inhibitors tested, 2 derivatives namely RKG162A and RKG1541 were bactericidal against M. tuberculosis. Both derivatives were mildly cytotoxic against macrophages. For cysteine protease inhibitors, 35 derivatives were tested. Four derivatives namely AXE1, AXE4, AXE5, and AXE29 were bactericidal whereas AXE2, AXE3, AXE35, and NAT47 were bacteriostatic.
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43

Gurjar, Purujit. "Design and Synthesis of Anti Cancer Agents that Inhibit Cysteine Proteases, Limit Oxidative Stress or Terminate Proliferation of BCR-ABL Expressing Cells". University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535635261401718.

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44

Lynas, John F. "The design, synthesis and kinetic characterisation of novel inhibitors of the serine and cysteine proteases". Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318767.

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45

Siles, Rogelio Pinney Kevin G. "Design, synthesis and biological evaluation of new anti-Cancer nitrogen-containing combretastatins and novel cysteine protease inhibitors for the treatment of Chagas". Waco, Tex. : Baylor University, 2005. http://hdl.handle.net/2104/3018.

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46

Mountz, Adele K. "The synthesis, characterization, and use of a protein-cysteine proteinase inhibitor complex for the study of endosome/lysosome fusion". Diss., Virginia Tech, 1994. http://hdl.handle.net/10919/38555.

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47

Schulze, Hüynck Jan [Verfasser], Gunther [Gutachter] Döhlemann e Stanislav [Gutachter] Kopriva. "Cysteine proteases and their inhibitors in microbe - maize root interactions / Jan Schulze Hüynck ; Gutachter: Gunther Döhlemann, Stanislav Kopriva". Köln : Universitäts- und Stadtbibliothek Köln, 2019. http://d-nb.info/1202920365/34.

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48

Schad, Caroline [Verfasser], e Tanja [Gutachter] Schirmeister. "Synthese und Testung neuartiger peptidomimetischer, selektiver Inhibitoren parasitärer Cystein-Proteasen / Caroline Schad. Gutachter: Tanja Schirmeister". Würzburg : Universität Würzburg, 2013. http://d-nb.info/1102822914/34.

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49

Kiggundu, Andrew. "Engineering plant cysteine protease inhibitors for the transgenic control of banana weevil, Cosmopolites sordidus (Germar) (Coleoptera : Curculionidae) and other coleopteran insects in transgenic plants". Thesis, Pretoria : [s.n.], 2008. http://upetd.up.ac.za/thesis/available/etd-01152009-155015.

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50

Yamamoto, Masaru. "Synthesis and oxidation studies of sulfur containing inhibitors for human leukocyte elastase : (2) synthesis of cyclic peptide analogs for tissue factor pathway inhibitor (TFPI) : Part 2 synthesis and evaluation of aziridinecarboxylic acid analogs as a new family of cysteine proteinase inhibitors". Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/25953.

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