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Title: Therapeutics development against the Apicomplexa parasites Plasmodium falciparum and Toxoplasma gondii
Author: Capper, Michael
ISNI:       0000 0004 6058 1388
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2015
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Apicomplexa parasites are the cause of two of the world’s most widespread diseases; malaria and toxoplasmosis. Malaria affects two billion people worldwide in some of the poorest regions of the world. Over a million people a year die from malaria, the majority of which are pregnant women or children under the age of 5. Plasmodium falciparum is by far the most lethal cause of malaria and is endemic to many regions of sub-Saharan Africa. Toxoplasma gondii is the most common parasitic infection of human brain and eyes and is suspected to affect one third of the world’s population. Rising drug resistance and the inadequacies of current treatments have spurred a global effort for the development of new therapies targeting these parasites Cytochrome bc1 (cyt. bc1) is a proven drug target for both treatment and prophylaxis of P. falciparum and T. gondii. Atovaquone, a potent broad- spectrum anti-parasitic drug, targets the Qo site, one of two active sites within cytochrome, b collapsing the mitochondrial membrane potential and killing the parasites. Single mutations within the Qo site render atovaquone ineffective and incidences of resistance are rising. Previous work has focussed on overcoming resistance through the design/redesign of compounds targeting the well understood Qo site. Here we show the binding modes of GSK’s next-generation antimalarial 4(1H)-pyridones and a novel 4(1H)-quinolone to the Qi site of cyt. bc1. These structures reveal the mechanism by which the compounds are able to overcome resistance and point in a new direction for antimalarial drug development. This work reaffirms the importance of structural observation in drug development. Merozoite surface protein 1–19 (MSP119) is an important target in vaccine development against malaria. Recent work has shown that cupredoxins bind MSP119 of P. falciparum and result in death for the parasite. Rusticyanin, the most potent of these, has been extensively studied and various mutants have been produced a range of redox potentials and acid stability properties. Here, initial studies of the complex between P. falciparum MSP119 and rusticyanin are carried out and analysed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General)