Screening of a chemogenetic library unveils dual-stage antimalarials with low cytotoxicity

ABSTRACT The global effort to eradicate malaria requires the development of drugs with novel mechanisms of action and differentiated pharmacological profiles. Both liver and blood phases of Plasmodium infection are essential for disease progression and transmission, making them primary targets for therapeutic intervention. In this study, we established a dual-luciferase reporter assay to simultaneously assess Plasmodium berghei liver-stage development and host cell viability. Screening a library of bioactive small molecules with annotated human targets revealed several inhibitors with potent liver-stage activity and minimal cytotoxicity. Further profiling against P. falciparum asexual blood stages identified compounds with dual-stage activity, underscoring their potential utility for development as either prophylactic or therapeutic agents. Knowledge of their human targets will facilitate investigation into host- or parasite- directed antimalarial mechanisms, thereby accelerating both biological insight and rational drug development. Our findings constitute a valuable resource for research on malaria biology and the discovery of next-generation antimalarials.