Plasmodium falciparum falcilysin as an emerging potential drug target for antimalarial drug discovery.

Malaria remains a significant global health challenge, with rising drug resistance highlighting the urgent need for new therapeutic targets. Falcilysin (FLN), a conserved zinc metalloprotease essential for Plasmodium falciparum survival, has a pivotal role in hemoglobin degradation and processing transit peptides in the apicoplast. Recent studies reveal a druggable hydrophobic allosteric pocket and clarified the dynamic conformations of FLN, guiding rational inhibitor design. Multiple small-molecule classes have shown potent FLN inhibition across biochemical, cellular, and in vivo models. Key challenges include dual-organelle localization, selectivity over human homologs, and translating hits into clinical candidates. Future efforts should expand chemical diversity, explore covalent and proteolysis-targeting chimera (PROTAC) modalities, adopt multitarget strategies, and integrate cryo-electron microscopy (EM) and artificial intelligence (AI)-driven modeling for improved drug design.