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Title: Inhibition of malaria de novo pyrimidine biosynthesis for drug development
Author: Bedingfield, Paul Thomas Peter
ISNI:       0000 0004 2717 529X
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
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In the absence of an effective vaccine there is ~ a considerable burden on drugs to provide protection from and treat the devastating disease, malaria. However, resistance has been seen to the majority of current antimalarials, making the continued development of new chemotherapeutics imperative. In this thesis dihydroorotate dehydrogenase (DHODH) is further examined as a potential drug target for the treatment of Plasmodium falciparum and Plasmodium vivax infection. DHODH is a key enzyme in de novo pyrimidine biosynthesis, the only pathway available to the parasites to generate vital pyrimidines. Site-directed mutagenesis, biochemical analysis and inhibitor testing on P. falciparum, P. vivax and Homo sapiens DHODH, in this study, identified residues and regions in the inhibitor binding sites important for the tight and selective binding of inhibitors. Specifically, a catalytic histidine, parasitic cysteine and phenylalanine residues, and an alpha helix that forms part of the inhibitor binding site are examined. Testing combinations of PfDHODH inhibitors with antimalarial drugs confirms that PfDHODH inhibition is an effective way to halt parasite growth without an adverse effect on the action of antimalarials. Three novel classes of PfDHODH inhibitors were identified with therapeutically relevant antiparasitic potency and selectivity to be explored further as antimalarial drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available