Aspartic Protease Targeting in Antimalarial Drug Discovery

Malaria remains a pressing global health challenge, with resistance to frontline therapies necessitating novel mechanisms of action. Aspartic proteases of Plasmodium species, known as plasmepsins, orchestrate critical stages of the parasite lifecycle including haemoglobin catabolism, processing of invasion and egress factors, and protein export. Targeting these enzymes holds promise for interventions against blood-stage parasites and transmission in mosquitoes. Early work on food-vacuole plasmepsins revealed functional redundancy in haemoglobin degradation, prompting efforts to inhibit multiple isoforms concurrently. More recent advances have focused on newly characterised isoforms such as plasmepsin X (PMX) and plasmepsin IX (PMIX), which regulate parasite egress and erythrocyte invasion via maturation of subtilisin-like proteases and organelle biogenesis. Structure-guided drug design has elucidated substrate recognition features, enabling the development of peptidomimetic and non-peptidic scaffolds with improved potency, oral bioavailability and selectivity over human proteases. Chemical biology approaches, including photoaffinity probes and fragment-based screening, have identified novel binding sites and allosteric pockets, expanding the toolkit for inhibitor discovery. Combined, these strategies underscore the diversity of aspartic protease functions and the potential to generate multi-target or dual-action compounds capable of overcoming resistance.

Research from Nature Portfolio

Recent structural analysis of Plasmodium falciparum plasmepsin V (PfPMV) has provided atomic-level detail of substrate engagement within the active site, uncovering unique PEXEL recognition determinants and an S4 subsite occlusion that precludes binding of classical pepsin inhibitors. Molecular dynamics simulations highlighted the roles of Glu179 and Gln222 in anchoring the PEXEL peptide, while comparative docking of HIV-1 protease inhibitors revealed features favourable for high-affinity binding. These insights form a foundational framework for the rational design of peptidomimetic inhibitors with enhanced specificity and pharmacokinetic properties.

Aspartic Protease Targeting in Antimalarial Drug Discovery publication trend

The graph below shows the total number of articles in aspartic protease targeting in antimalarial drug discovery across all publications each year (not limited to Nature Index journals).

Technical terms

Aspartic protease: An enzyme using two aspartate residues to hydrolyse peptide bonds.

Plasmepsin: A family of Plasmodium-encoded aspartic proteases essential for parasite survival.

Egress: The process by which malaria parasites exit host erythrocytes after replication.

Invasion: Entry of merozoites into new red blood cells to establish infection.

Peptidomimetic: A compound that mimics peptide structure to inhibit proteases.

Photoaffinity labelling: A chemical biology technique using light-activated probes to covalently tag target proteins.

References

1. Malaria parasite plasmepsins: More than just plain old degradative pepsins. Journal of Biological Chemistry (2020).
2. Genetic Disruption of the Plasmodium falciparum Digestive Vacuole Plasmepsins Demonstrates Their Functional Redundancy*. Journal of Biological Chemistry (2004).
3. Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Science (2017).
4. Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D. European Journal of Medicinal Chemistry (2018).
5. Understanding the structural basis of substrate recognition by Plasmodium falciparum plasmepsin V to aid in the design of potent inhibitors. Scientific Reports (2016).
6. Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity. Journal of Medicinal Chemistry (2023).
7. Fragment-based virtual screening identifies novel leads against Plasmepsin IX (PlmIX) of Plasmodium falciparum: Homology modeling, molecular docking, and simulation approaches. Frontiers in Pharmacology (2024).
8. Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in Plasmodium falciparum. RSC Chemical Biology (2024).