Figure 7.

Exoerythrocytic-stage active compounds display unique potencies during exoerythrocytic-stage EEF development. (a) Diagram illustrating the major stages of malaria parasite exoerythrocytic-stage development, including invasion, parasitophorous vacuole membrane (PVM) remodeling, trophozoite development, and EEF schizont development. During the first 4 h after sporozoite invasion, the parasite dramatically remodels its parasitophorous vacuole membrane by degrading host-cell-derived proteins and at the same time inserting its own parasite-derived proteins.⁶ During the next 18 h, the sporozoites transform from their elongated motile form to round, nonmotile, and metabolically active trophozoites. The trophozoites undergo impressive nuclear replication starting at around 24 h postinfection, displaying one of the fastest replication rates known to eukaryotic organisms to develop into mature EEFs.⁶ Drug treatments 1–6, corresponding to compound incubation during the exoerythrocytic developmental stages indicated, are shown. (b) Pb-Luc IC₅₀ data for established antimalarial compounds (atovaquone and pyrimethamine), antimalarials in development (GNF179, KDU691, DDD107498), and the three MMV Malaria Box compounds (MMV666693, MMV007160, and MMV665916) added during Pb-Luc exoerythrocytic-stage development in a modified 384-well luciferase-based assay (discussed in Materials and Methods) are shown. Likewise, the Pb-Luc IC₅₀ fold changes normalized to the 2–50 h drug-treated controls are shown and colored based on the indicated heat map.