Proteases of the malaria parasite Plasmodium falciparum have been targeted for drug discovery for decades. The P. falciparum genome encodes ten aspartic proteases called plasmepsins, which are involved in diverse cellular processes. In this work we address the roles of two of these plasmepsins, plasmepsins IX and X (PM IX and X), the two least studied aspartic proteases in blood stage malaria parasites till date. We explore the essentiality of these proteases in parasite development, attempt to identify their substrates and the ability to drug them. We show that PM IX is essential for erythrocyte invasion, acting on rhoptry secretory organelle biogenesis. When PM IX is knocked down, rhoptry formation is impaired but the substrate(s) of PM IX responsible for this phenotype have not yet been discovered.
We have suspected targets and the progress made on implicating these important substrates will be reported in this work.
In contrast, PM X is essential for both egress and invasion, controlling maturation of the subtilisin-like serine protease SUB1 in exoneme secretory vesicles. SUB1, synthesized as a zymogen needs to be converted to its active form after an initial self-cleavage. We explore the mechanism by which PM X converts the intermediate SUB1 species to its active form. Interestingly, we discover that PM X cleaves the intramolecular self-inhibiting prodomain part of the protein probably allowing a second activation step. We proceed to determine the cleavage sites that could prevent the inhibitory function of the prodomain. We have identified compounds with potent antimalarial activity targeting PM X, including a compound known to have oral efficacy in a mouse malaria model.
|Advisor:||Goldberg, Daniel E.|
|Commitee:||Sibley, David, Kutluay, Sebla, Djuranovic, Segej, Bubeck-Wardenburg, Juliane|
|School:||Washington University in St. Louis|
|Department:||Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)|
|School Location:||United States -- Missouri|
|Source:||DAI-B 82/7(E), Dissertation Abstracts International|
|Keywords:||Egress, Invasion, Plasmepsins, Plasmodium, Proteases, Rhoptries|
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