دورية أكاديمية
Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites.
| العنوان: | Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites. |
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| المؤلفون: | Timothy James Russell, Erandi K De Silva, Valerie M Crowley, Kathryn Shaw-Saliba, Namita Dube, Gabrielle Josling, Charisse Flerida A Pasaje, Irene Kouskoumvekaki, Gianni Panagiotou, Jacquin C Niles, Marcelo Jacobs-Lorena, C Denise Okafor, Francisco-Javier Gamo, Manuel Llinás |
| المصدر: | PLoS Pathogens, Vol 18, Iss 10, p e1010887 (2022) |
| بيانات النشر: | Public Library of Science (PLoS), 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Immunologic diseases. Allergy LCC:Biology (General) |
| مصطلحات موضوعية: | Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5 |
| الوصف: | Plasmodium parasites are reliant on the Apicomplexan AP2 (ApiAP2) transcription factor family to regulate gene expression programs. AP2 DNA binding domains have no homologs in the human or mosquito host genomes, making them potential antimalarial drug targets. Using an in-silico screen to dock thousands of small molecules into the crystal structure of the AP2-EXP (Pf3D7_1466400) AP2 domain (PDB:3IGM), we identified putative AP2-EXP interacting compounds. Four compounds were found to block DNA binding by AP2-EXP and at least one additional ApiAP2 protein. Our top ApiAP2 competitor compound perturbs the transcriptome of P. falciparum trophozoites and results in a decrease in abundance of log2 fold change > 2 for 50% (46/93) of AP2-EXP target genes. Additionally, two ApiAP2 competitor compounds have multi-stage anti-Plasmodium activity against blood and mosquito stage parasites. In summary, we describe a novel set of antimalarial compounds that interact with AP2 DNA binding domains. These compounds may be used for future chemical genetic interrogation of ApiAP2 proteins or serve as starting points for a new class of antimalarial therapeutics. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1553-7366 1553-7374 |
| Relation: | https://doaj.org/toc/1553-7366; https://doaj.org/toc/1553-7374 |
| DOI: | 10.1371/journal.ppat.1010887 |
| URL الوصول: | https://doaj.org/article/32dbbe0804b44aea83886f60da9addc8 |
| رقم الأكسشن: | edsdoj.32dbbe0804b44aea83886f60da9addc8 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 15537366 15537374 |
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| DOI: | 10.1371/journal.ppat.1010887 |