Malaria continues to be one of the most devastating human diseases despite many efforts to limit its spread by prevention of infection or by pharmaceutical treatment of patients. We have conducted a screen for antiplasmodial compounds by using a natural product library. Here we report on cyclomarin A as a potent growth inhibitor of Plasmodium falciparum and the identification of its molecular target, diadenosine triphosphate hydrolase (PfAp3Aase), by chemical proteomics. Using a biochemical assay, we could show that cyclomarin A is a specific inhibitor of the plasmodial enzyme but not of the closest human homologue hFHIT. Co-crystallisation experiments demonstrate a unique binding mode of the inhibitor. One molecule of cyclomarin A binds a dimeric PfAp3Aase and prevents the formation of the enzyme⋅substrate complex. These results validate PfAp3Aase as a new drug target for the treatment of malaria. We have previously elucidated the structurally unrelated regulatory subunit ClpC1 of the ClpP protease as the molecular target of cyclomarin A in Mycobacterium tuberculosis. Thus, cyclomarin A is a rare example of a natural product with two distinct and specific modes of action.

The inside cover picture shows the malaria parasite Plasmodium falciparum at the late schizont stage in a red blood cell. It is filled with invasive merozoites. The natural product cyclomarin A is a potent inhibitor of the growth of P. falciparum. It binds to the plasmodial enzyme diadenosine triphosphate (Ap3A) hydrolase—but not to the closest human homologue—and prevents the formation of an enzyme⋅substrate complex. Our results validate the hydrolase as a new drug target for the treatment of malaria. More details can be found in the Communication by E. K. Schmitt et al. on page 2433 in Issue 17, 2015 (DOI: 10.1002/cbic.201500472).