Targeting Metabolic Pathways in Plasmodium falciparum

Plasmodium falciparum, the most lethal agent of human malaria, depends on a limited repertoire of metabolic routes that differ fundamentally from those of its human host. Crucial among these are purine salvage pathways, which supply the parasite with essential nucleotides for DNA and RNA synthesis, and specialised lipid-modification systems that regulate protein localisation and function. The absence of de novo purine synthesis renders enzymes such as purine nucleoside phosphorylase indispensable, while co- and post-translational lipid additions—myristoylation and palmitoylation—underpin parasite growth, invasion and stage conversion. Inhibiting these pathways has therefore emerged as a powerful strategy to starve and immobilise the parasite without harming human cells. Recent advances in structural biology, chemical synthesis and phenotypic screening have yielded highly selective enzyme inhibitors and analogue libraries that combine potent antiplasmodial activity with low host toxicity. This integrated approach holds promise for next-generation antimalarial regimens that circumvent existing drug resistance.

Research from Nature Portfolio

Recent studies have exploited structure-guided design to create hybrid inhibitors that bind selectively to parasite myristoyl-transferases. By merging chemical motifs from earlier scaffolds, researchers achieved sub-nanomolar affinity for N-myristoyltransferase and demonstrated dose-dependent clearance of blood-stage P. falciparum in vitro, while crystal structures revealed unique parasite-specific binding pockets. In parallel, novel sugar-modified nucleoside analogues have been prepared and profiled against multiple P. falciparum strains. Morpholino-nucleoside hybrids and thio-substituted derivatives display submicromolar inhibitory concentrations, clear parasitaemia in murine models and exhibit minimal cytotoxicity toward mammalian cells. These advances lay the groundwork for rapid translation into combination therapies that target both blood and liver stages.

Targeting Metabolic Pathways in Plasmodium falciparum publication trend

The graph below shows the total number of articles in targeting metabolic pathways in plasmodium falciparum across all publications each year (not limited to Nature Index journals).

Technical terms

Metabolic pathway: A series of enzymatic reactions within the parasite that converts nutrients into essential biomolecules.

N-myristoyltransferase (NMT): An enzyme that catalyses the attachment of a 14-carbon myristoyl group to proteins, influencing membrane association and protein function.

Purine nucleoside phosphorylase (PNP): A key enzyme in the purine salvage pathway that cleaves nucleosides to release purine bases for nucleotide synthesis.

Palmitoylation: The reversible addition of a 16-carbon palmitoyl group to cysteine residues in proteins, regulating their stability, localisation and interactions.

Nucleoside analogue: A synthetic compound resembling natural nucleosides, designed to interfere with parasite nucleotide metabolism.

References

1. In vitro and in vivo antiplasmodial evaluation of sugar-modified nucleoside analogues. Scientific Reports (2023).
2. Identification and structural validation of purine nucleoside phosphorylase from Plasmodium falciparum as a target of MMV000848. Journal of Biological Chemistry (2023).
3. Analysis of Protein Palmitoylation Reveals a Pervasive Role in Plasmodium Development and Pathogenesis. Cell Host & Microbe (2012).
4. Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors. Cell Chemical Biology (2019).