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Genetic and chemical validation of Trypanosoma brucei adenosine kinase, the intracellular target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]-morpholine

Defense Thèse de doctorat : Univ. Genève, 2013 - Sc. 4595 - 2013/09/25
Abstract Human African Trypanosomiasis (HAT) is caused by African trypanosomes, a fatal disease if untreated. New safe and potent drugs are needed to treat HAT as the few available drugs are still unsatisfactory. The aim of the thesis is to understand the antiproliferative effect of compound 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]-morpholine (1) which has recently been identified to hyperactivate Trypanosoma brucei adenosine kinase (TbAK). To this end, an ion-pair HPLC/UV method was developed and used to analyse changes in adenine purine levels of trypanosomes during different growth phases in absence or presence of 1. Several strains of Trypanosoma brucei were tested, e.g. i) the wild type strain, ii) a tetracycline inducible ak overexpression strain (hypothesizing that the presence of 1 is similar to overexpression of TbAK), and iii) a tetracycline inducible null mutant ak overexpression strain to provide insight into the effect of non-physiological high levels of TbAK on the parasite nucleoside/nucleotide metabolism.
Keywords Trypanosoma bruceiEnergy chargeGrowth phasesHPLCPurine poolAdenosine kinaseGene deletionGene expression regulation
URN: urn:nbn:ch:unige-400462
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Thesis (28.1 MB) - public document Free access
Research group Biochimie pharmaceutique
Project FNS: 3100A0-120566/1
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GRAVEN, Patricia. Genetic and chemical validation of Trypanosoma brucei adenosine kinase, the intracellular target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]-morpholine. Université de Genève. Thèse, 2013. doi: 10.13097/archive-ouverte/unige:40046 https://archive-ouverte.unige.ch/unige:40046

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Deposited on : 2014-09-08

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