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

Diplôme Thèse Genetic and chemical validation of Trypanosoma brucei adenosine kinase, the intracellular target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]-morpholine eng 2013-09-25 author Graven Patricia 595276 director Perozzo Remo 625237 director Scapozza Leonardo 600318 10.13097/archive-ouverte/unige:40046 urn:nbn:ch:unige-400462 Sc. 4595 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. Trypanosoma brucei Energy charge Growth phases HPLC Purine pool Adenosine kinase Gene deletion Gene expression regulation Dewey 615 Swiss National Science Foundation 3100A0-120566/1 CH 31 Section des sciences pharmaceutiques 17 false 880 Biochimie pharmaceutique 6715a5a8-7f9b-4228-92cd-dfbec68f6992 Thesis Public Thesis_PG_10rdversion.pdf 29501802 application/pdf openAccess Faculté des sciences / Section des sciences pharmaceutiques

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Genetic and chemical validation of Trypanosoma brucei adenosine kinase, the intracellular target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]-morpholine				2013	1,098	340

Archive ouverte UNIGE

Graven, Patricia