High-Throughput Screening to Identify Inhibitors of Importin α.

The global burden of malaria and toxoplasmosis has been limited by the use of efficacious anti-parasitic agents, however, emerging resistance in species and 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 and have promise as targets for small molecule inhibitors. We use high-throughput screening to identify agents able to inhibit IMPα binding to a NLS, identifying a number of compounds that inhibit binding in the µM-nM range, through direct binding to IMPα, as shown in thermostability assays. Of these, BAY 11-7085 is shown to be a specific inhibitor of IMPα-NLS recognition. Importantly, a number of the inhibitors limited growth by both and . 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.