High-Throughput Screening to Identify Inhibitors of <i>Plasmodium falciparum</i> Importin α
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 ta...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/7/1201 |
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| author | Sujata B. Walunj Manisha M. Dias Chhaminder Kaur Kylie M. Wagstaff Vishakha Dey Caroline Hick Swati Patankar David A. Jans |
| author_facet | Sujata B. Walunj Manisha M. Dias Chhaminder Kaur Kylie M. Wagstaff Vishakha Dey Caroline Hick Swati Patankar David A. Jans |
| author_sort | Sujata B. Walunj |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T11:59:58Z |
| format | Article |
| id | doaj.art-ccfbb4b2e04f4d22aa8fc6b8fabed32c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T11:59:58Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-ccfbb4b2e04f4d22aa8fc6b8fabed32c2023-11-30T23:04:52ZengMDPI AGCells2073-44092022-04-01117120110.3390/cells11071201High-Throughput Screening to Identify Inhibitors of <i>Plasmodium falciparum</i> Importin αSujata B. Walunj0Manisha M. Dias1Chhaminder Kaur2Kylie M. Wagstaff3Vishakha Dey4Caroline Hick5Swati Patankar6David A. Jans7Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaNuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaMolecular Parasitology Laboratory, Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, IndiaNuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaMolecular Parasitology Laboratory, Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, IndiaMonash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, AustraliaMolecular Parasitology Laboratory, Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, IndiaNuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaThe 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.https://www.mdpi.com/2073-4409/11/7/1201<i>Plasmodium falciparum</i>malaria<i>Toxoplasma gondii</i>toxoplasmosisimportinsnuclear import inhibitors |
| spellingShingle | Sujata B. Walunj Manisha M. Dias Chhaminder Kaur Kylie M. Wagstaff Vishakha Dey Caroline Hick Swati Patankar David A. Jans High-Throughput Screening to Identify Inhibitors of <i>Plasmodium falciparum</i> Importin α Cells <i>Plasmodium falciparum</i> malaria <i>Toxoplasma gondii</i> toxoplasmosis importins nuclear import inhibitors |
| title | High-Throughput Screening to Identify Inhibitors of <i>Plasmodium falciparum</i> Importin α |
| title_full | High-Throughput Screening to Identify Inhibitors of <i>Plasmodium falciparum</i> Importin α |
| title_fullStr | High-Throughput Screening to Identify Inhibitors of <i>Plasmodium falciparum</i> Importin α |
| title_full_unstemmed | High-Throughput Screening to Identify Inhibitors of <i>Plasmodium falciparum</i> Importin α |
| title_short | High-Throughput Screening to Identify Inhibitors of <i>Plasmodium falciparum</i> Importin α |
| title_sort | high throughput screening to identify inhibitors of i plasmodium falciparum i importin α |
| topic | <i>Plasmodium falciparum</i> malaria <i>Toxoplasma gondii</i> toxoplasmosis importins nuclear import inhibitors |
| url | https://www.mdpi.com/2073-4409/11/7/1201 |
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