Malaria Parasite's Gene Control Mechanism Unveiled: New Therapeutic Avenues Emerge

A multinational team, including Penn State scientists, has discovered critical regulatory control mechanisms in *Plasmodium falciparum* [plaz-MOH-dee-uh fal-SIP-uh-ruhm], the deadliest malaria parasite. The research, published in *Nature* on February 19, reveals new opportunities for developing therapeutic approaches against malaria, a disease affecting millions globally. Malaria is caused by *Plasmodium* parasites, transmitted to humans by infected mosquitoes. According to Manuel Llinás [man-WELL lee-NAS], Ernest C. Pollard Professor in Biotechnology at Penn State, the parasites undergo developmental transitions controlled by gene expression changes to survive and replicate. Understanding these molecular processes is crucial for combating the pathogen at different stages. The study identifies a protein, PfSnf2L [P-F-S-N-F-2-L], that modulates the *Plasmodium* genome structure, enabling precise timing of gene expression. Genes are encoded in DNA within chromosomes, which consist of DNA wrapped around proteins, forming chromatin. For genes to be functional, proteins must access the DNA through the chromatin to produce RNA. Llinás explained that chromatin can be open or closed, allowing or preventing access of regulatory proteins to the DNA. Chromatin remodeling ensures the correct genes are expressed at the right stages of the *Plasmodium* life cycle. This epigenetic control doesn't alter the DNA itself. The team found that PfSnf2L, a chromatin remodeler, is essential for the stage-specific expression of genes in *Plasmodium falciparum*. They identified a small molecule inhibitor, NH125 [N-H-1-2-5], that blocks PfSnf2L function and kills the parasite, also preventing the development of sexual-stage parasites, thus blocking transmission by mosquitoes. Maria Theresia Watzlowik [mah-REE-ah teh-REH-zee-ah VATS-loh-vik] of the University of Regensburg stated that PfSnf2L is essential for *P. falciparum* to dynamically adjust gene expression, offering opportunities for therapies that inhibit life cycle progression and block transmission. The researchers used a multidisciplinary approach to uncover the role of NH125. Ritwik Singhal [RIT-wik SING-hal], doctoral candidate at Penn State, noted that NH125 targets both asexual and sexual stages of the parasite, making it remarkable, especially in multiple strains. The findings advance the understanding of gene regulation during the *Plasmodium* life cycle and offer practical applications. Gernot Längst [GER-not LENGST] of the University of Regensburg stated that targeting epigenetic regulation could disrupt the parasite's capacity to modulate gene expression, reducing the likelihood of resistance development. In 2022, malaria caused an estimated 247 million infections and over 600,000 deaths. Markus Meissner [MAR-kus MY-sner] of the Ludwig-Maximilians-University in Munich stated that future work will focus on testing small molecules that inhibit the parasite's epigenetic machinery and exploring their effectiveness in preclinical models.