Plasmepsins as Antimalarial Drug Targets—Then, Now, and the Future

Malaria is a devastating disease caused by Plasmodium parasites. Plasmodium parasites express ten cathepsin D-like aspartyl proteases, called plasmepsins (PMs). These PMs have diverse roles fulfill diverse functions throughout the parasite's lifecycle, though several exhibit functional redundancies. Among them, PMV, PMIV, and PMX are essential for asexual stage development, positioning them as prime candidates for antimalarial development. This review synthesizes current knowledge on PM biology and highlights the pivotal role of PM inhibitors in validating these proteases as therapeutic targets. Learnings from past research on PMs coupled with advances in experimental approaches have largely steered drug discovery efforts toward the development of dual PMIX/PMX inhibitors. Highlighted is an overview of the developmental trajectory of PM inhibitors, their progress to date, and their potential integration into future antimalarial therapies aimed at both prevention and treatment.