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dc.contributor.advisorWalkinshaw, Malcolm
dc.contributor.advisorGilmore, Linda
dc.contributor.authorVasquez Valdivieso, Montserrat Guadalupe
dc.date.accessioned2016-11-25T12:09:04Z
dc.date.available2016-11-25T12:09:04Z
dc.date.issued2014-06-28
dc.identifier.urihttp://hdl.handle.net/1842/17980
dc.description.abstractTrypanosomatid parasites cause a wide range of so-called neglected diseases which affect over 27 million people every year. Current treatments are toxic and prone to resistance; therefore, it is imperative to identify novel protein targets and to develop more efficient treatments. Phosphofructokinase (PFK) is the third enzyme in glycolysis, and its reciprocal enzyme in gluconeogenesis is fructose-1,6-bisphosphatase (FBPase); in trypanosomatid parasites (Trypanosoma brucei [Tb], Trypanosoma cruzi [Tc] and Leishmania [Lm] species), both enzymes are recognised drug targets. This thesis describes biochemical and structural studies on these two allosteric enzymes that have been studied with two main purposes: 1) To understand their intrinsic behaviour. The allosteric mechanism of T. brucei PFK is described with the help of two novel crystal structures: TbPFK with the allosteric activator AMP, and mutant A288D located in the effector site. These studies have provided a better understanding of the effect of evolution on the allostery of PFK; and have introduced the first reproducible crystallisation of TbPFK via its A288D mutant. 2) To find novel inhibitors using in silico and high-throughput methods, and to investigate how the intrinsic behaviour relates to the mechanism of inhibition. Nanomolar selective inhibitors against TbPFK and TcPFK have been obtained and optimised to a novel family with low micromolar inhibitory activity against cultured parasites. Crystal structures with three of these inhibitors on TbPFK have helped us understand the structure-activity relationship. Moreover, novel crystal structures of TcPFK and LmFBPase, as well as reproducible crystallisation conditions for the latter enzyme and a mutant of TbPFK (A288D) will undoubtedly facilitate future drug discovery on these targets. Our long-term aim of finding novel drugs against sleeping sickness has been supported by the Wellcome Trust which has recently granted a Seeding Drug Discovery Award with the name “Optimisation of a trypanosome phosphofructokinase lead series to give candidates for treatment of the trypanosomatid based neglected disease Human African Trypanosomiasis”.en
dc.contributor.sponsorotheren
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionBrimacombe, K. R., Walsh, M. J., Vásquez-Valdivieso, M. G., Morgan, H. P., McNae, I., Fothergill- Gilmore, L. A., Michels, P. A. M., Auld, D. S., Simeonov., A., Walkinshaw, M. D., Shen., M., Boxer, M. B. (2014) Identification of ML251, a potent inhibitor of T. brucei and T. cruzi phosphofructokinase. ACS Medicinal Chemistry Letters 5, 12-17.en
dc.relation.hasversionWalsh, M. J., Brimacombe, K. R., Vásquez-Valdivieso, M. G., Auld, D. S., M. G., Simeonov., A., Morgan, H. P., Fothergill-Gilmore, L. A., Michels, P. A. M., Walkinshaw, M. D., Shen., M., Boxer, M. B. (2013) Identification of Selective Inhibitors of Phosphofructokinase as Lead Compounds Against Trypanosomiasis. Probe Reports from the NIH Molecular Libraries Program.en
dc.subjectinhibitorsen
dc.subjecttrypanosomiasisen
dc.subjectcrystallographyen
dc.titleIdentification of selective inhibitors of phosphofructokinase and fructose bisphosphatase as lead compounds against trypanosomatidsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31en
dcterms.accessRightsRestricted Access


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