# Plasmepsin X function in Plasmodium

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $381,250

## Abstract

PROJECT SUMMARY / ABSTRACT
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. We have
recently 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 get out of the host red blood
cell (RBC) and invade fresh RBCs. We have identified a class of aspartic
protease inhibitors called aminohydantoins that appear 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. We
believe that PMX is an exciting new drug target but need to better characterize its
function to inform ongoing drug development and enhance our understanding of
parasite biology.
To address these questions, aim 1 will 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. Aim 2 will focus on what PMX interacts with. Is SUB1
the only substrate? What else is in the secretory vesicle called the exoneme,
where PMX and SUB1 both reside? Aim 3 will address the question of how PMX
itself gets activated. Our preliminary data suggest that there must be an
upstream enzyme. We will characterize the processing and look for a maturase.
We anticipate that the proposed studies will yield great insight into the
pathogenesis of malaria and will point the way to new therapies for this
devastating disease.

## Key facts

- **NIH application ID:** 9829079
- **Project number:** 5R01AI138447-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Daniel E. Goldberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-01-02 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829079

## Citation

> US National Institutes of Health, RePORTER application 9829079, Plasmepsin X function in Plasmodium (5R01AI138447-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9829079. Licensed CC0.

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