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dc.contributor.authorMeredith, Emma Louise
dc.date.accessioned2016-06-16T11:23:35Z
dc.date.available2016-06-16T11:23:35Z
dc.date.issued2016-01-28
dc.date.submitted2016-06-14T14:20:23.723Z
dc.identifier.citationMeredith, E.L. 2016 :Evaluating quinone based compounds for their antitrypanosomatid properties, Queen Mary University of London.en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/12898
dc.descriptionPhDen_US
dc.description.abstractHuman African trypanosomiasis (HAT) is caused by the protozoan parasite Trypanosoma brucei. The use of existing drug regimens is controversial as they are toxic, have limited efficacy with resistance on the rise. Therefore, there is an urgent need for new therapies. One group of compounds that are being exploited or evaluated in treating infectious diseases and cancer are the quinones, with these agents mediating their cytotoxic activities by acting as prodrugs or inhibiting key metabolic pathways. Here, we report the screening of a quinone-based compound library against bloodstream form T. brucei and against the related parasites Trypanosoma cruzi and Leishmania major, the causative agents of Chagas disease and cutaneous leishmaniasis, respectively. This analysis demonstrated that the most potent compounds were those that possessed an aziridinyl 1,4-benzoquinone (ABQs) core with the most effective displaying a 50% growth inhibitory concentrations of < 1 μM against all three pathogens. Using RH1, the archetypal ABQ, as a selective agent, a combination of a T. brucei whole genome loss of function assay and drug selection studies demonstrated that these compounds function as prodrugs with the activation mechanism catalysed by a type I nitroreductase (NTR). Functional studies using T. brucei that express altered levels of NTR further demonstrated the importance of this enzyme in activating the majority of quinone-based moieties tested. Using genetic approaches, we next demonstrated that following NTRmediated activation the resultant products go on to promote formation of interstrand crosslinks (ICLs) within the parasites’ genomes: T. brucei lacking the DNA repair enzyme SNM1, a nuclease that specifically fixes ICL damage, were more susceptible to ABQs than controls. In conclusion, ABQs are potent antiparasitic prodrugs although mammalian toxicity studies indicate these compounds may not be suitable potential therapies for systemic infections although they are of interest as genetic tools for probing gene function.
dc.description.sponsorshipBBSRC Doctorial Training Studentship.en_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectBiological and Chemical Sciencesen_US
dc.subjectHuman African trypanosomiasisen_US
dc.subjectquinonesen_US
dc.subjectantiparasitic prodrugsen_US
dc.titleEvaluating quinone based compounds for their antitrypanosomatid propertiesen_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


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