High-Throughput Screening to Identify Inhibitors of Plasmodium falciparum Importin α

• Published in: Cells (Basel, Switzerland) Switzerland), 2022-04, Vol.11 (7), p.1201
• Main Authors: Walunj, Sujata B, Dias, Manisha M, Kaur, Chhaminder, Wagstaff, Kylie M, Dey, Vishakha, Hick, Caroline, Patankar, Swati, Jans, David A
• Format: Article
• Language: English
• Subjects: alpha Karyopherins - antagonists & inhibitors; Antiparasitic agents; Disease control; Drug resistance; Erythrocytes; Gene amplification; High-throughput screening; High-Throughput Screening Assays; importins; Infections; Localization; Malaria; nuclear import inhibitors; Nuclear Localization Signals - metabolism; Parasitic diseases; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - metabolism; Protein Binding; Protein expression; Proteins; Severe acute respiratory syndrome coronavirus 2; Therapeutic applications; Therapeutic targets; Thermal stability; Toxoplasma gondii; Toxoplasmosis; Vectors (Biology); Viral infections
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11071201

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.