The Ivermectin Related Compound Moxidectin Can Target Apicomplexan Importin α and Limit Growth of Malarial Parasites

Signal-dependent transport into and out of the nucleus mediated by members of the importin (IMP) superfamily is crucial for eukaryotic function, with inhibitors targeting IMPα being of key interest as anti-infectious agents, including against the apicomplexan Plasmodium species and Toxoplasma gondii, causative agents of malaria and toxoplasmosis, respectively. We recently showed that the FDA-approved macrocyclic lactone ivermectin, as well as several other different small molecule inhibitors, can specifically bind to and inhibit P. falciparum and T. gondii IMPα functions, as well as limit parasite growth. Here we focus on the FDA-approved antiparasitic moxidectin, a structural analogue of ivermectin, for its IMPα-targeting and anti-apicomplexan properties for the first time. We use circular dichroism and intrinsic tryptophan fluorescence measurements to show that moxidectin can bind directly to apicomplexan IMPαs, thereby inhibiting their key binding functions at low μM concentrations, as well as possessing anti-parasitic activity against P. falciparum in culture. The results imply a class effect in terms of IMPα's ability to be targeted by macrocyclic lactone compounds. Importantly, in the face of rising global emergence of resistance to approved anti-parasitic agents, the findings highlight the potential of moxidectin and possibly other macrocyclic lactone compounds as antimalarial agents.