The majority of human malaria and malaria deaths are caused by the parasitic pathogen Plasmodium falciparum. The immense global burden of malaria, combined with the rising prevalence of drug resistance to inexpensive antimalarials, is driving the need for identification of new drugs and novel therapeutic targets. Proteases play diverse and essential roles throughout the parasite lifecycle; however, only a handful of the predicted proteases of P. falciparum have been characterized. Thus, proteases represent an underexploited potential target for the treatment of malaria.
In this thesis I will describe two projects that attempt to advance our understanding of both the function and the drug target potential of P. falciparum proteases. In Part I, the P. falciparum proteasome is discussed. Although the proteasome is a known drug target of P. falciparum, toxicity resulting from cross-reactivity of inhibitors with the host proteasome has hindered development. The first identification of a potent and selective inhibitor of the P. falciparum proteasome with reduced host toxicity is presented.
In Part II, previously uncharacterized proteases involved in the regulation of ubiquitin and ubiquitin-like posttranslational modifiers are discussed. The first biochemical characterization of a small ubiquitin-related modifier (SUMO) protease from P. falciparum, PfSENP1, is presented. Furthermore, a new class of small molecule inhibitors against this target was identified and found to inhibit parasite replication. The unique substrate sequence specificity of PfSENP1, coupled with the apparent essential role of this protease in the blood stage life cycle, suggests PfSENP1 may represent a new protease drug target. Taken together, these studies suggest that both the parasite proteasome and PfSENP1 are potential targets for future drug development.
|School Location:||United States -- California|
|Source:||DAI-B 70/10, Dissertation Abstracts International|
|Keywords:||Malaria, Parasite, Plasmodium falciparum, Protease|
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