Importin α inhibitors act against the differentiated stages of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii.

This article focuses on evaluating small molecule inhibitors targeting importin α (IMPα)-dependent nuclear import as a therapeutic strategy against multiple life cycle stages of the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii. The study demonstrates that Bay 11-7082, a structural analogue of Bay 11-7085, inhibits IMPα interactions with nuclear localization signals (NLSs) in both parasites and reduces T. gondii tachyzoite viability, while GW5074 and Caffeic Acid Phenethyl Ester (CAPE) inhibit nuclear transport in P. falciparum blood stages. CAPE notably impairs gametocyte maturation in P. falciparum, and Bay 11-7082/7085 weakly inhibit T. gondii bradyzoite differentiation, suggesting nuclear import blockade can affect parasite differentiation. These findings provide proof of concept that targeting nuclear import is a viable approach for developing therapeutics against differentiated and proliferative stages of these parasites, which are often resistant to existing drugs.