Family of Parasite Proteins Offers Possible Route for Malaria Therapy

A group of researchers from the Francis Crick Institute and the Gulbenkian Institute for Molecular Medicine has identified a family of proteins in Plasmodium falciparum that could serve as a target for new malaria treatments. The study, published in Nature Microbiology, describes how this group of exported proteins, known as FIKK kinases, is critical to the parasite’s ability to infect human red blood cells.

Malaria continues to cause significant morbidity and mortality worldwide, with over 200 million cases and approximately 500,000 deaths annually. While antimalarial drugs are available, the effectiveness of many is threatened by increasing drug resistance.

Exported proteins help remodel red blood cells

During infection, P. falciparum injects a fraction of its proteins into host red blood cells, altering their surface and internal structure. This remodeling process helps the infected cells adhere to blood vessels and other red blood cells, a mechanism that can lead to clot formation.

Among the exported proteins are FIKK kinases, which alter host or parasite proteins to either activate or suppress their function. By analyzing over 2,000 clinical samples, the researchers found that most of the 21 FIKK kinases were highly conserved. Eighteen showed evidence of evolutionary pressure against mutations, implying these proteins are essential to the parasite’s life cycle in humans.

Functional differences and structural clues

The team produced each of the FIKK kinases in bacterial cells to identify their specific targets. Although each kinase had a distinct protein target, one stood out for its ability to modify tyrosine, an amino acid involved in key cellular signaling pathways. This type of modification has not previously been observed in malaria parasites.

Using both experimental data and the protein structure prediction tool AlphaFold 2, the researchers discovered that the target specificity of each FIKK kinase is influenced by subtle differences in a flexible loop region. While these variations enable each kinase to interact with different targets, the team also observed structural features shared across the kinase family. These conserved elements, which distinguish FIKK kinases from human counterparts, could provide a basis for therapeutic intervention.

Screening for broad inhibition

To explore therapeutic potential, the researchers collaborated with GlaxoSmithKline to screen a library of compounds that inhibit human kinases. Out of this screen, three molecules showed activity against FIKK kinases, and two were able to inhibit most of the tested kinases in vitro.

The ability to block all FIKK kinases simultaneously may offer a way to prevent the parasite from modifying host cells. Further development of these molecules could lead to a new class of antimalarial drugs that are less prone to resistance.

The majority of the experimental work was carried out at the Francis Crick Institute, with additional contributions from the Gulbenkian Institute for Molecular Medicine and other research groups, including Université Laval in Canada.

Reference: Belda H, Bradley D, Walport L, et al. The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound. Nat Microbiol. 2025. doi: 10.1038/s41564-025-02017-4

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