Protein Arginine Methyltransferase Inhibitors Target Multiple Stages of <i>Plasmodium falciparum</i> Parasites <i>In Vitro</i>

The ongoing rise in antimalarial drug resistance underscores the urgent need for new drug candidates that specifically target novel mechanisms. Malaria parasites employ various epigenetic strategies to regulate gene expression throughout their complex life cycle, with histone lysine acetylation and methylation being well-studied and targeted by new antiplasmodials. By contrast, arginine methylation remains poorly explored. <i>Plasmodium falciparum</i> possesses three protein arginine methyltransferases (PRMTs) that maintain a unique and combinatorial histone arginine methylation landscape. Here, we present a chemical repositioning strategy to evaluate the efficacy of known PRMT inhibitors against malaria parasites. We identified a potent compound, TC-E 5003, which is active across multiple stages of parasite development. PfPRMT1 was proposed as the most likely target of TC-E 5003, with a distinct structure-activity relationship demonstrated by TC-E 5003 analogs from a hit expansion campaign. The chemotype exhibits a clear pharmacophore that elucidates the compound's mechanism of action. Overall, these findings open a new pathway for identifying multistage active antiplasmodial candidates targeting a novel protein family in <i>P. falciparum</i>.