Family of Parasite Proteins Presents New Potential Malaria Treatment Target

Malaria, which is responsible for over 500,000 deaths and more than 200 million infections annually, is caused by Plasmodium parasites that invade red blood cells. Drug resistance remains a significant obstacle to effective treatment.

A newly published study in Nature Microbiology describes how a family of exported proteins, known as FIKK kinases, in the malaria-causing parasite Plasmodium falciparum plays a key role in enabling it to infect human hosts.

The findings may inform strategies for developing drugs that reduce the risk of resistance by targeting multiple essential proteins simultaneously.

Kinase family supports parasite adaptation to humans

Researchers from the Francis Crick Institute and the Gulbenkian Institute for Molecular Medicine examined over 2,000 P. falciparum samples. Their analysis revealed that 18 of the 21 FIKK kinase genes showed signs of purifying selection, suggesting that these genes are essential for the parasite’s ability to infect humans.

FIKK kinases are among the approximately 10% of P. falciparum proteins exported into host red blood cells during infection. These proteins remodel host cells to enhance parasite survival, including altering cell adhesion properties that lead to vascular blockages.

By expressing the FIKK proteins in bacterial systems, the team demonstrated that the kinases each target different substrates. One kinase was shown to modify tyrosine residues – an activity not previously observed in this parasite group – indicating the evolution of novel interactions with host cell signaling mechanisms.

Protein structure reveals drug target potential

Using the AlphaFold 2 software, the researchers mapped the structure of FIKK kinases and identified a flexible loop region that contributes to substrate specificity. Despite the variation in this loop across different kinases, recurring structural motifs were found that distinguish these proteins from human kinases.

These motifs may represent a therapeutic vulnerability, enabling the design of compounds that inhibit multiple FIKK kinases without affecting human proteins.

“About 1 million years ago, Plasmodium crossed from birds into great apes. With this cross, the FIKK kinase family expanded to enable infection of our closest relatives," said Moritz Treeck, head of the Cell Biology of Host-Pathogen Interaction Laboratory, formerly at the Crick and now at the Gulbenkian Institute for Molecular Medicine.

"A relatively short time ago, Plasmodium falciparum crossed from great apes to humans, and we’ve shown that the kinases needed for survival in great apes are still required for survival in humans," he said. "This suggests that targeting shared properties of FIKK kinases could stop P. falciparum from remodelling the host cell.”

Candidate inhibitors block kinase activity

The team collaborated with GlaxoSmithKline to screen a library of small molecules originally developed to inhibit human kinases. From this screen, three molecules were identified that interact with FIKK kinases, and two of these were shown to inhibit most of the proteins in vitro.

These results suggest that broad-spectrum inhibition of FIKK kinases could interfere with the parasite's ability to remodel host cells, potentially offering a new approach to malaria treatment. The next steps will involve modifying the identified molecules to improve their suitability for use in clinical settings.

Reference: Belda H, Bradley D, Christodoulou E, 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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