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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Evaluace vlastností polymerních konjugátů specificky vážících proteiny pro použití v molekulární biologii / Evaluation of the properties of polymer conjugates which specifically bind proteins and can be used in molecular biology

Parolek, Jan January 2015 (has links)
During last three decades, a great effort was invested to the development of polymer conjugates of low molecular drugs with the aim to improve the specific targeting of drugs to diseased tissues, cells and organs. The main reason for this effort was the fact that high molecular weight copolymers have a favourite distribution profile in tissues and organisms. A linker between a polymer backbone and drug has very important role: it is possible to synthesize a biodegradable linker, which can be enzymatically hydrolyzed. Conversely, there is a possibility to synthesize an inert linker, resistant to the hydrolysis. Proper choice of the suitable precursor- polymer is also essential, hence it has to accomplish all of the stringent demands for biocompatibility. Macromolecular polymer-drug conjugates tend to accumulate in solid tumors because of the so called enhanced permeability and retention (EPR) effect. There is a whole range of possible applications of high molecular polymer-drug conjugates. In the introduction part of this thesis, I summarize potential use of drugs based on poly(N-(2-hydroxypropyl)methacrylamide) (HPMA) copolymers. Moreover, I introduce some therapeutically important proteins used in experimental drug discovery. In our laboratory, we have developed a concept of HPMA copolymers...
2

Conditional Activation and Synergistic Enhancement of Smac Mimetic Peptides with Nucleic Acids

Altrichter, Yannic 14 March 2022 (has links)
Smac-Mimetika (SMCs) sind eine Klasse von Tetrapeptid-abgeleiteten Medikamenten, die dem homodimeren, pro-apoptotischen Protein Smac nachempfunden sind. Sie binden und hemmen die Apoptose-Inhibitoren (IAPs), eine Klasse von anti-apoptotischen Proteinen, die von vielen medikamentenresistenten Krebszellen überexprimiert werden. In dieser Arbeit wurden Strategien zur Steigerung und Kontrolle der Aktivität von SMCs durch Konjugation an Oligonukleotide (ON) untersucht. ONs wie Desoxyribonukleinsäure (DNA) oder das peptidbasierte Analogon Peptidnukleinsäure (PNA) bieten einzigartige Erkennungseigenschaften, die zur Detektion und/oder zur Modulation der Expression krebsspezifischer Genprodukte genutzt werden können. Letzteres kann z. B. mit Antisense-Oligonukleotiden (ASOs) erreicht werden, kurzen einzelsträngigen DNA- oder RNA-Molekülen, die die Translation einer komplementären Zielsequenz blockieren. Im ersten Teil der Arbeit wurden Konjugate aus SMCs und ASOs auf Synergie-Effekte getestet. Viele menschliche Krebszelllinien sind gegen SMCs resistent, weil andere anti-apoptotische Proteine wie das zelluläre FLICE-ähnliche Protein (c-FLIP) als Ausfallsicherung wirken. Es konnte gezeigt werden, dass diese Resistenz durch Kupplung eines SMC an ein anti-c-FLIP ASO überwunden werden kann. Im zweiten Teil wurden kurze ON-Sonden verwendet, um ein templiertes Reaktionssystem zur gezielten Aktivierung eines SMCs in Gegenwart von X-linked Apoptose-Inhibitor (XIAP) mRNA zu erzeugen. Es wurden zwei verschiedene Ansätze untersucht: Ein templierter Acyl-Transfer, bei dem hochaffine, bivalente SMCs aus niedrig affinen, monovalenten Vorläufern erzeugt werden und eine Demaskierung der für die Bindungsaffinität von SMCs entscheidenden, N-terminalen Aminogruppe durch templierte Reduktion eines Azids. Für die zweite Strategie wurden zwei verschiedene Reaktionen verglichen, die Staudinger-Reduktion mit Phosphinen und eine katalytische Photoreduktion mit einem Ruthenium-Komplex. / Smac mimetic compounds (SMCs) are a class of tetrapeptide-derived drugs, modelled after the homodimeric, pro-apoptotic protein Smac. They bind and antagonize Inhibitor of Apoptosis Proteins (IAPs), a class of anti-apoptotic proteins overexpressed by many drug-resistant cancer cells. In this work, strategies to enhance and control the activity of SMCs by conjugating them to oligo-nucleotides (ON) were investigated. ONs like deoxyribonucleic acid (DNA) or the peptide-based analog peptide nucleic acid (PNA) offer unique recognition properties that can be used to detect and/or modulate the expression of cancer-specific gene products. The latter can be achieved with antisense oligonucleotides (ASOs), short single-stranded DNA or RNA molecules that block the translation of a complementary sequence of interest. In the first part of this work, conjugates between SMCs and ASOs were tested for synergy. Many human cancer cell lines are resistant to SMCs because other anti-apoptotic proteins like the cellular FLICE-like protein (c-FLIP) act as a failsafe. It could be demonstrated that by joining an SMC with an anti-c-FLIP ASO this resistance can be overcome. In the second part, short ON probes were used to create a templated reaction system to conditionally activate an SMC in the presence of x-linked inhibitor of apoptosis (XIAP) mRNA. Two different approaches were explored: A templated acyl transfer that yields high affinity bivalent SMCs from low affinity, monovalent precursors and unmasking of the N-terminal amino group, which is crucial for the binding affinity of SMCs, by templated reduction of an azide. For the second strategy, two different chemistries were compared, Staudinger reduction with phosphines and a catalytic photoreduction using a ruthenium complex.
3

Vývoj nanochemických nástrojů cílících receptory nádorového mikroprostředí / Development of nanochemical tools targeting receptors in the tumor microenvironment

Blažková, Kristýna January 2022 (has links)
Development of nanochemical tools targeting receptors in the tumor microenvironment Targeting the receptors in the tumor microenvironment is crucial for the future development of targeted therapies, precision medicine and immunotherapy of cancer. The options available now are, however, limited by the availability of specific ligands. The advances in the field strongly rely on the use of antibodies and genetic modifications of immune cells. Availability of small molecules targeting the receptors of interest would allow further development of alternative strategies as well as deepen our understanding of the underlying mechanisms of cancer development, progression and clearance. In the search for new small-molecule ligands and their use for receptor targeting, the prostate-specific membrane antigen (PSMA) and the immune receptors CD3 and CD64 were selected as model targets. The selected method - the phage display of bicyclic peptides - utilizes chemical modification of the displayed three-cysteine peptides to achieve their cyclization and formation of bicycles. The panning of a peptide library displayed on the phages and probed with PSMA revealed a reproducibly-selected amino acid sequence. Interestingly, the phage clone carrying this sequence was a specific binder of PSMA, but the synthesized peptide alone...
4

Glutamátkarboxypeptidasa II jako cíl farmaceutického zásahu a molekulární adresa pro léčbu nádorových onemocnění / Glutamate Carboxypeptidase II as a Drug Target and a Molecular Address for Cancer Treatment

Knedlík, Tomáš January 2018 (has links)
Glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA), is a membrane metallopeptidase overexpressed on most prostate cancer cells. Additionally, GCPII also attracted neurologists' attention because it cleaves neurotransmitter N-acetyl-L-aspartyl-L-glutamate (NAAG). Since NAAG exhibits neuroprotective effects, GCPII may participate in a number of brain disorders, which were shown to be ameliorated by GCPII selective inhibitors. Therefore, GCPII has become a promising target for imaging and prostate cancer targeted therapy as well as therapy of neuronal disorders. Globally, prostate cancer represents the second most prevalent cancer in men. With the age, most men will develop prostate cancer. However, prostate tumors are life threatening only if they escape from the prostate itself and start to spread to other tissues. Therefore, considerable efforts have been made to discover tumors earlier at more curable stages as well as to target aggressive metastatic cancers that have already invaded other tissues and become resistant to the standard treatment. Since patients undergoing a conventional therapy (a combination of chemotherapy and surgery) suffer from severe side effects, more effective ways of treatment are being searched for. Novel approaches include selective...

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