In a groundbreaking study that could revolutionize the fight against malaria, researchers from the Francis Crick Institute and the Gulbenkian Institute for Molecular Medicine (GIMM) have unraveled the evolutionary secrets of a family of parasite proteins known as FIKK kinases. These proteins, exported by the malaria-causing parasite Plasmodium falciparum, play a pivotal role in the parasite’s ability to infect human red blood cells and evade immune defenses. By dissecting the molecular mechanisms underlying these kinases, scientists have opened new avenues for therapeutic interventions that could outmaneuver the persistent problem of drug resistance in malaria treatment.
Malaria continues to claim over half a million lives annually, predominantly caused by P. falciparum, the deadliest of malaria parasites responsible for more than 95% of malaria mortality worldwide. Traditional treatments, although initially effective, face the constant threat of evolving parasite resistance, making it imperative to identify novel targets that can disrupt the parasite’s complex interplay with human host cells. The study, published in Nature Microbiology, sheds light on the molecular evolution and functional specificity of the FIKK kinase family, offering a promising target for next-generation antimalarial drugs.
A hallmark of P. falciparum infection is its ability to remodel host red blood cells to enhance survival and transmission. Approximately 10% of the parasite’s proteins are exported into the host cell during infection, radically altering its structure and adhesiveness to blood vessel walls and other infected cells, which can lead to severe pathological clots. Among these exported proteins, FIKK kinases stand out due to their enzymatic activity; they function as protein kinases, modifying host and parasite proteins through phosphorylation, thereby regulating essential pathways crucial for parasite survival in the human host.
By analyzing an extensive dataset of over two thousand P. falciparum genomes obtained from infected individuals, the research team uncovered strong evolutionary conservation in 18 out of 21 FIKK kinase genes. This selective preservation points to their indispensable roles in maintaining the parasite’s infectivity and hints at their contribution to the parasite’s adaptation from nonhuman primates to humans. These findings suggest that FIKK kinases have been central in the parasite’s evolutionary journey, reinforcing the hypothesis that targeting these kinases could cripple the parasite’s ability to thrive within human hosts.
To characterize their functions, each FIKK kinase was expressed recombinantly in bacterial cells, allowing detailed biochemical investigations. The experiments revealed that despite sharing structural frameworks, individual FIKK kinases exhibit distinct substrate specificities, targeting an array of host cell proteins. Remarkably, one kinase demonstrated the unprecedented ability to phosphorylate tyrosine residues in proteins, a modification not previously attributed to malaria parasites. This discovery insinuates an evolutionary refinement enabling the parasite to hijack host cell signaling pathways that rely on tyrosine phosphorylation, a mechanism widespread in mammalian cellular communication.
The molecular basis for this functional diversity was further elucidated using computational modeling and state-of-the-art protein structure prediction algorithms, including AlphaFold 2. The data pointed towards subtle yet critical variations within a flexible loop region of the kinase domain as the determinant for binding specificity. While these loop regions differ enough to diversify function, they also share conserved structural motifs that distinguish FIKK kinases from their human counterparts. This unique feature identifies them as attractive selective drug targets, minimizing potential off-target effects on human kinases.
With these insights, the team embarked on high-throughput screening of compounds known to inhibit human kinases, collaborating with pharmaceutical giant GlaxoSmithKline. This approach unveiled three molecules with promising inhibitory properties against FIKK kinases. Two of these compounds inhibited the majority of FIKK family members in vitro, highlighting the potential of designing broad-spectrum antimalarials that disable multiple kinases simultaneously. This multiplex inhibition strategy can reduce the likelihood of drug resistance, a significant hurdle in current malaria therapies.
The concept of blocking an entire kinase family rather than focusing on individual proteins represents a paradigm shift in antimalarial drug design. Moritz Treeck, head of the research laboratory at GIMM, emphasized the evolutionary context, noting that the FIKK kinase family expanded as Plasmodium parasites transitioned from infecting birds to great apes approximately one million years ago. This expansion likely facilitated adaptation to the complex physiology of mammalian hosts, culminating in P. falciparum’s recent jump to humans. Persisting reliance on these kinases underscores their viability as universal intervention points across related Plasmodium species.
Hugo Belda, co-first author of the study, highlighted the interdisciplinary nature of the research, which entailed collaborative efforts spanning molecular evolution, biochemistry, structural biology, and chemical inhibition studies. The team’s comprehensive approach produced a holistic view of P. falciparum evolutionary biology and pathogenicity. Belda also underscored the clinical implications, suggesting that compounds targeting multiple kinases simultaneously may represent a robust avenue to circumvent the rapid emergence of drug-resistant Plasmodium strains seen in single-target treatments.
Central to this research was the integration of cutting-edge technologies, including protein-protein interaction analyses, proteomics, and flow cytometry, which facilitated precise dissection of the parasite’s cellular machinery. The collaboration extended beyond the Francis Crick Institute and GIMM, encompassing international partners such as Christian Landry’s team at Université Laval in Canada. This multidisciplinary alliance exemplifies how converging expertise can accelerate translational science aimed at addressing one of humanity’s oldest scourges.
Moving forward, the research team intends to focus on refining the identified compounds for therapeutic use in humans. This includes optimizing their chemical properties to enhance bioavailability, target specificity, and safety profiles. Should these efforts succeed, they could pave the way for a new class of antimalarial drugs that strategically incapacitate the parasite’s exported kinase machinery, offering fresh hope in the global campaign against malaria.
This seminal work not only advances our understanding of parasite biology and host adaptation but also elevates the importance of targeting evolutionary conserved protein families in infectious diseases. By leveraging both evolutionary insights and structural biology, the study marks a critical step toward innovative and durable malaria treatments.
Subject of Research: Cells
Article Title: The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound
News Publication Date: 19-May-2025
Web References: http://dx.doi.org/10.1038/s41564-025-02017-4
References: Belda, H., & Bradley, D., et al. (2025). The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound. Nature Microbiology. https://doi.org/10.1038/s41564-025-02017-4
Keywords: Malaria, Plasmodium, FIKK kinases, kinase inhibitors, protein phosphorylation, drug resistance, parasitic diseases, host-pathogen interaction
