Last Updated: 27/05/2025
Plasmepsin X function in Plasmodium
Objectives
The aims of this project are:
- examine the specificity of PMX and will address the question of whether SUB1 maturation by PMX is direct. Biochemical assays using isolated PMX with SUB1 as a substrate and with a random peptide library will be performed;
- focus on PMX interactions, including determining if SUB1 is the only substrate and what else might be in the secretory vesicle called the exoneme, where PMX and SUB1 both reside; and
- investigate how PMX itself gets activated, as preliminary data suggest the presence of an upstream enzyme. The processing will be characterized, and a maturase will be sought.
Malaria afflicts several hundred million and kills more than 600,000 people each year, mostly children in Sub-Saharan Africa. Aspartic proteases have long been antimalarial targets of interest. A large number of aspartic protease inhibitors that are potent against parasites in culture have been developed, but their specific targets have been elusive. Plasmepsin X (PMX) is one of the least characterized aspartic proteases found in asexual intraerythrocytic malaria parasites. Recently, it was found that PMX is a key enzyme for intraerythrocytic parasite egress and invasion. It activates the master trigger subtilysin-like protease 1 (SUB1), launching proteolytic events that allow merozoites to exit the host red blood cell (RBC) and invade fresh RBCs.
A class of aspartic protease inhibitors called aminohydantoins has been identified, which appears to kill parasites through PMX blockade, preventing SUB1 activation and impairing egress/invasion. PMX knockdown phenocopies inhibitor action. One of the inhibitors has favorable pharmacokinetic properties and gives oral cure in a rodent malaria model. PMX is considered an exciting new drug target, but further characterization of its function is needed to inform ongoing drug development and enhance understanding of parasite biology.
The proposed studies are anticipated to yield significant insights into the pathogenesis of malaria and point the way to new therapies for this devastating disease.
Jan 2018 — Dec 2023
$1.91M
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