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Natural compounds isolated from plants at the Faculty of Pharmacy in Hradec Králové as potential inhibitors of aldo-ketoreductase 1A1 (AKR1A1)
Karásková, Jitka ; Novotná, Eva (advisor) ; Raisová Stuchlíková, Lucie (referee)
Charles Universtity Pharmaceutical Faculty in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Jitka Karásková Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Natural compounds isolated from plants at the Faculty of Pharmacy in Hradec Králové as potential inhibitors of aldo-ketoreductase 1A1 (AKR1A1) Aldo-keto reductase 1A1 is an enzyme belonging to the aldo-keto reductase superfamily. It is a monomeric, cytosolic enzyme that is able to reduce carbonyl groups within a wide range of substrates. The enzyme is expressed in almost every tissue in the body, most represented in hepatocytes, renal cells and salivary glands, where it contributes to the reduction of endogenous substrates and the first phase of biotransformation of xenobiotics. AKR1A1 catalyzes NADPH-dependent reduction of aldehydes and ketones to their corresponding primary and secondary alcohols. Enzyme substrates include, for example, mevalonate; anthracycline antibiotics doxorubicin or daunorubicin; some pro-carcinogens that are activated by the reaction into carcinogens, such as: trans- dihydrodiol metabolites of polycyclic aromatic hydrocarbons. Generally, it is involved in the metabolism of lipids and carbohydrates that contain an aldehyde function. The increased expression and activity of AKR1A1 has been...
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Synthesis of peptidic inhibitors targeting PA-PB1 interface of influenza RNA polymerase
Palacková, Miroslava ; Machara, Aleš (advisor) ; Veselý, Jan (referee)
The submitted Thesis deals with preparation of a hexapeptides inhibiting protein-protein interaction of PA-PB1 subunits of influenza RNA polymerase. Crucial part of the Thesis represent modifications of particular small hexapeptide at its two "hot spots". It means at positions that significantly contribute to the binding of both subunits. These modifications resulted in preparation of two series of distinct hexapeptides. With regards to the fact that one designed hexapeptide contains unnatural and commercially unavailable amino acids this amino acid had to be prepared from simple building blocks. Apart from aforementioned work the Thesis also covers effort to prepared bicyclic peptide that contains sequences of peptidic inhibitor of protein-protein interactions and also cell-penetration peptide. Key words: synthesis, peptides, inhibitors, influenza, polymerase
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The synthesis of stable O-acetyl-adenosine diphosphoribose analogs and inhibitors of sirtuins
Dvořáková, Marcela ; Vaněk, Tomáš (advisor) ; Jindřich, Jindřich (referee) ; Krečmerová, Marcela (referee)
Acetylated adenosine diphosphoribose (OAADPR) is a product of protein deacetylation catalysed by class III of histone deacetylases called sirtuins. Sirtuins deacetylate histones and other proteins by unique mechanism coupled with consumption of stoichiometric amount of NAD+ . Sirtuins and OAADPR are implicated in the regulation of gene transcription, signalling and metabolic pathways and lifespan extension, thus preventing the development of age-related diseases. Even though, sirtuins are well studied, the exact biological role of OAADPR remains mainly unknown. Its further exploration is restricted by OAADPR's proneness to enzymatic hydrolysis. Therefore, non-hydrolysable analogues of OAADPR are needed to establish its biological function. These analogues are also expected to be competitive inhibitors of sirtuins, which may reveal their potential as therapeutic agents. A series of OAADPR analogues in which the acetate moiety was replaced with alkylcarbonate functionality has been synthesized. The studies of alkylcarbonate migration on furanoside scaffold have established the stability of alkylcarbonate vs. acetate under various conditions. Generally, alkylcarbonates are more stable than acetate under acidic or neutral conditions whereas under basic conditions they seem to be less stable....
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Cathepsin C of the blood fluke Schistosoma mansoni
Oupicová, Irena ; Konvalinka, Jan (advisor) ; Ryšlavá, Helena (referee)
Blood flukes of the genus Schistosoma cause schistosomiasis, one of the most serious parasitic diseases. Cathepsin C (EC 3.4.14.1) is a digestive enzyme of the blood flukes and a potential drug target. This cysteine protease has not been studied in detail yet. In this thesis, cathepsin C activity was detected in the extract of adult blood flukes S. mansoni and S. japonicum. Inhibitory specificity of these enzymes was determined using of set of selective inhibitors of mammalian cathepsins. Cathepsins C were visualized on SDS-PAGE gels with fluorescent proteomic probe. Furthermore, recombinant cathepsin C of S. mansoni (SmCC) was prepared by homologous expression in the yeast Pichia pastoris. (In Czech)
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