Work

Repurposed small-molecule inhibitors of Plasmodium falciparum calmodulins disrupt calcium homeostasis

Year: 2026

Type: article

Abstract: Calcium signaling is essential for the survival of Plasmodium falciparum , yet few components of its Ca 2+ regulatory machinery have been chemically validated as antimalarial drug targets. Here, we report the structure-guided identification of small molecule inhibitors targeting a parasite specific subset of calmodulin and calmodulin-like proteins that lack close human orthologs. Virtual screening followed by biophysical validation revealed that the drugs Econazole, Carvedilol, and Deschloro-Lapatinib selectively engage three parasite calmodulin paralogs ( Pf Cam200, Pf Cam300, and Pf Cam400) and inhibit their Ca 2+ -binding activity. Direct binding was confirmed by bio-layer interferometry and calcium-binding assays, demonstrating micromolar affinities and functional inhibition. Chemical perturbation of parasite calmodulins disrupts food vacuole directed Ca 2+ trafficking, induces redistribution of intracellular Ca 2+ , and results in stage specific arrest of parasite development. Confocal imaging localizes Pf Cam200, Pf Cam300, and Pf Cam400 in proximity to the digestive vacuole transporters Pf CRT and Pf MDR1, supporting a mechanistic link between calmodulin function and vacuolar Ca 2+ homeostasis. Collectively, these findings establish parasite calmodulins as chemically tractable targets and demonstrate the utility of repurposed small molecules as probes to interrogate essential Ca 2+ -dependent pathways in malaria parasites.

Source: International Journal for Parasitology Drugs and Drug Resistance

DOI: 10.1016/j.ijpddr.2026.100673