(400e) Unraveling Non-Classical Pathways in the Suppression of ?-Hematin Crystal Growth

Antimalarial drugs inhibit the intraerythrocytic stage of malaria parasite primarily by suppressing hematin crystallization, a vital heme detoxification pathway of the parasite. While classical mechanisms of hematin crystal growth such as dislocation and two-dimensional nucleation have been well characterized through in-situ AFM studies, non-classical pathways remain less understood. Our study identified a novel non-classical mechanism in which β-hematin growth is driven by the deposition of mesoscopic hematin-rich clusters on the crystal surface, resulting in significantly accelerated crystal growth. To evaluate how recently introduced antimalarial drugs and their metabolites, including tafenoquine, lumefantrine, and the heme-dihydroartemisinin adduct, suppress hematin crystallization, we combine time-resolved in situ AFM with dynamic light scattering and Brownian microscopy. We observed distinct mechanisms, by which each drug interacts with hematin crystals and their nucleation precursors. Our findings offer valuable insights into non-classical inhibition and may inform the design of novel drugs and strategies for more effective antimalarial therapies.