New Insights on RAP Proteins Open Doors for Malaria Treatment Advances

A groundbreaking study led by researchers at the University of California, Riverside (UCR) has unveiled critical insights into the Plasmodium falciparum parasite, which causes the deadliest form of malaria. This research, published in *Cell Reports* on July 1, 2025, focuses on the regulation of gene expression by RAP (RNA-binding domain Abundant in Apicomplexans) proteins located in the apicoplast, a unique organelle found in this parasite. The study suggests that targeting these proteins could pave the way for the next generation of highly specific antimalarial therapies.

Under the leadership of Dr. Karine Le Roch, a professor in the Department of Molecular, Cell, and Systems Biology, the UCR team identified two key RAP proteins, PfRAP03 and PfRAP08, which play essential roles in the parasite's survival. "This is the first time anyone has shown how RAP proteins in the apicoplast directly interact with ribosomal RNA and transfer RNA," Dr. Le Roch stated. The research revealed that the loss of either protein resulted in the death of the parasite, underscoring their critical function in the regulation of protein synthesis within the apicoplast.

The study builds on previous findings about RAP proteins in parasite mitochondria and represents the first detailed mechanistic analysis of their function within the apicoplast. This structure, which is unique to apicomplexan parasites, includes not only P. falciparum but also Toxoplasma gondii and Babesia species, making it an attractive target for drug development that would not harm human cells. Dr. Le Roch highlighted the evolutionary significance of RAP proteins, noting that while humans possess six such proteins, parasites like P. falciparum have more than 20. This difference suggests that RAP proteins may be crucial for parasite-specific functions, further solidifying their potential as drug targets.

The implications of this research extend beyond malaria. Dr. Le Roch pointed out that the insights gained could also inform treatment strategies for other apicomplexan diseases, such as toxoplasmosis and babesiosis, which pose significant health risks, particularly to vulnerable populations like pregnant women. By revealing the vulnerabilities in the molecular machinery that these parasites rely on, the researchers aim to develop therapies that can intervene before these diseases take hold.

Although there are currently no drugs targeting RAP proteins, Dr. Le Roch’s team is working towards elucidating the three-dimensional structures of these RNA-protein complexes. This endeavor is a vital step toward structure-guided drug design, aiming to create effective treatments with minimal side effects by focusing on essential, parasite-specific proteins that lack human counterparts.

The research was conducted by a collaborative team at UCR, including first author Thomas Hollin, along with Zeinab Chahine, Steven Abel, Todd Lenz, Jacques Prudhomme, Caitlyn Marie Ybanez, and Anahita S. Abbaszadeh. The Stowers Institute for Medical Research in Kansas City, Missouri, contributed with Charles Banks and Laurence Florens, while Jacquin C. Niles and Charisse Flerida A. Pasaje from the Massachusetts Institute of Technology also participated. The research was financially supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and UCR.

In conclusion, this study not only advances our understanding of P. falciparum but also sets the stage for innovative therapeutic strategies against malaria and other related diseases. By targeting the unique RAP proteins within the apicoplast, researchers hope to harness a novel approach in the fight against these globally significant health threats.