The Potent Antiplasmodial Calmodulin-Antagonist Trifluoperazine Inhibits Plasmodium falciparum Calcium-Dependent Protein Kinase 4

Due to their critical involvement in the execution of the malaria parasite developmental pattern both in the mosquito vector and in the human host, Plasmodium calcium-dependent protein kinases (CDPKs) are considered promising candidates for the development of new tools to block malaria transmission. We report here that the phenothiazine trifluoperazine non-competitively inhibits Plasmodium falciparum CDPK4 in the micromolar range while other calmodulin antagonists only marginally affect the enzyme activity, and we propose the inhibition mechanism. Our results demonstrate that selective enzyme inhibition is achievable by targeting its calmodulin-like domain. This observation could be exploited for the discovery of innovative phenothiazine-based CDPK inhibitors of potential medical interest.