| Summary: | The global burden of malaria and toxoplasmosis has been limited by the use of efficacious anti-parasitic agents, however, emerging resistance in <i>Plasmodium</i> species and <i>Toxoplasma gondii</i> threatens disease control worldwide, implying that new agents/therapeutic targets are urgently needed. Nuclear localization signal (NLS)-dependent transport into the nucleus, mediated by members of the importin (IMP) superfamily of nuclear transporters, has shown potential as a target for intervention to limit viral infection. Here, we show for the first time that IMPα from <i>P. falciparum</i> and <i>T. gondii</i> have promise as targets for small molecule inhibitors. We use high-throughput screening to identify agents able to inhibit <i>P. falciparum</i> IMPα binding to a <i>P. falciparum</i> NLS, identifying a number of compounds that inhibit binding in the µM-nM range, through direct binding to <i>P. falciparum</i> IMPα, as shown in thermostability assays. Of these, BAY 11-7085 is shown to be a specific inhibitor of <i>P. falciparum</i> IMPα-NLS recognition. Importantly, a number of the inhibitors limited growth by both <i>P. falciparum</i> and <i>T. gondii</i>. The results strengthen the hypothesis that apicomplexan IMPα proteins have potential as therapeutic targets to aid in identifying novel agents for two important, yet neglected, parasitic diseases.
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