Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites
<jats:p><jats:italic>Plasmodium</jats:italic> 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...
| Main Authors: | , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023
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| Online Access: | https://hdl.handle.net/1721.1/147888 |
| _version_ | 1811073734256099328 |
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| author | Russell, Timothy James De Silva, Erandi K Crowley, Valerie M Shaw-Saliba, Kathryn Dube, Namita Josling, Gabrielle Pasaje, Charisse Flerida A Kouskoumvekaki, Irene Panagiotou, Gianni Niles, Jacquin C Jacobs-Lorena, Marcelo Denise Okafor, C Gamo, Francisco-Javier Llinás, Manuel |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Russell, Timothy James De Silva, Erandi K Crowley, Valerie M Shaw-Saliba, Kathryn Dube, Namita Josling, Gabrielle Pasaje, Charisse Flerida A Kouskoumvekaki, Irene Panagiotou, Gianni Niles, Jacquin C Jacobs-Lorena, Marcelo Denise Okafor, C Gamo, Francisco-Javier Llinás, Manuel |
| author_sort | Russell, Timothy James |
| collection | MIT |
| description | <jats:p><jats:italic>Plasmodium</jats:italic> 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 <jats:italic>in-silico</jats:italic> 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 <jats:italic>P</jats:italic>. <jats:italic>falciparum</jats:italic> trophozoites and results in a decrease in abundance of log<jats:sub>2</jats:sub> fold change > 2 for 50% (46/93) of AP2-EXP target genes. Additionally, two ApiAP2 competitor compounds have multi-stage anti-<jats:italic>Plasmodium</jats:italic> 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.</jats:p> |
| first_indexed | 2024-09-23T09:37:47Z |
| format | Article |
| id | mit-1721.1/147888 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:37:47Z |
| publishDate | 2023 |
| publisher | Public Library of Science (PLoS) |
| record_format | dspace |
| spelling | mit-1721.1/1478882023-02-07T03:44:43Z Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites Russell, Timothy James De Silva, Erandi K Crowley, Valerie M Shaw-Saliba, Kathryn Dube, Namita Josling, Gabrielle Pasaje, Charisse Flerida A Kouskoumvekaki, Irene Panagiotou, Gianni Niles, Jacquin C Jacobs-Lorena, Marcelo Denise Okafor, C Gamo, Francisco-Javier Llinás, Manuel Massachusetts Institute of Technology. Department of Biological Engineering <jats:p><jats:italic>Plasmodium</jats:italic> 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 <jats:italic>in-silico</jats:italic> 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 <jats:italic>P</jats:italic>. <jats:italic>falciparum</jats:italic> trophozoites and results in a decrease in abundance of log<jats:sub>2</jats:sub> fold change > 2 for 50% (46/93) of AP2-EXP target genes. Additionally, two ApiAP2 competitor compounds have multi-stage anti-<jats:italic>Plasmodium</jats:italic> 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.</jats:p> 2023-02-06T15:05:54Z 2023-02-06T15:05:54Z 2022 2023-02-06T14:51:11Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147888 Russell, Timothy James, De Silva, Erandi K, Crowley, Valerie M, Shaw-Saliba, Kathryn, Dube, Namita et al. 2022. "Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites." PLoS Pathogens, 18 (10). en 10.1371/JOURNAL.PPAT.1010887 PLoS Pathogens Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science (PLoS) PLoS |
| spellingShingle | Russell, Timothy James De Silva, Erandi K Crowley, Valerie M Shaw-Saliba, Kathryn Dube, Namita Josling, Gabrielle Pasaje, Charisse Flerida A Kouskoumvekaki, Irene Panagiotou, Gianni Niles, Jacquin C Jacobs-Lorena, Marcelo Denise Okafor, C Gamo, Francisco-Javier Llinás, Manuel Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites |
| title | Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites |
| title_full | Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites |
| title_fullStr | Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites |
| title_full_unstemmed | Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites |
| title_short | Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites |
| title_sort | inhibitors of apiap2 protein dna binding exhibit multistage activity against plasmodium parasites |
| url | https://hdl.handle.net/1721.1/147888 |
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