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A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1
Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently ne...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Springer Singapore
2020
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733455/ https://www.ncbi.nlm.nih.gov/pubmed/33311461 http://dx.doi.org/10.1038/s41421-020-00215-4 |
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| author | Huang, Zhenghui Li, Ruoxi Tang, Tongke Ling, Dazheng Wang, Manjiong Xu, Dandan Sun, Maoxin Zheng, Lulu Zhu, Feng Min, Hui Boonhok, Rachasak Ding, Yan Wen, Yuhao Chen, Yicong Li, Xiaokang Chen, Yuxi Liu, Taiping Han, Jiping Miao, Jun Fang, Qiang Cao, Yaming Tang, Yun Cui, Jie Xu, Wenyue Cui, Liwang Zhu, Jin Wong, Gary Li, Jian Jiang, Lubin |
| author_facet | Huang, Zhenghui Li, Ruoxi Tang, Tongke Ling, Dazheng Wang, Manjiong Xu, Dandan Sun, Maoxin Zheng, Lulu Zhu, Feng Min, Hui Boonhok, Rachasak Ding, Yan Wen, Yuhao Chen, Yicong Li, Xiaokang Chen, Yuxi Liu, Taiping Han, Jiping Miao, Jun Fang, Qiang Cao, Yaming Tang, Yun Cui, Jie Xu, Wenyue Cui, Liwang Zhu, Jin Wong, Gary Li, Jian Jiang, Lubin |
| author_sort | Huang, Zhenghui |
| collection | PubMed |
| description | Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites. JX21108 was developed from chemical optimization of quisinostat, a histone deacetylase inhibitor. We identified P. falciparum histone deacetylase 1 (PfHDAC1), an epigenetic regulator essential for parasite growth and invasion, as a molecular target of JX21108. PfHDAC1 knockdown leads to the downregulation of essential parasite genes, which is highly consistent with the transcriptomic changes induced by JX21108 treatment. Collectively, our data support that PfHDAC1 is a potential drug target for overcoming multidrug resistance and that JX21108 treats malaria and blocks parasite transmission simultaneously. |
| format | Online Article Text |
| id | pubmed-7733455 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2020 |
| publisher | Springer Singapore |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-77334552020-12-17 A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1 Huang, Zhenghui Li, Ruoxi Tang, Tongke Ling, Dazheng Wang, Manjiong Xu, Dandan Sun, Maoxin Zheng, Lulu Zhu, Feng Min, Hui Boonhok, Rachasak Ding, Yan Wen, Yuhao Chen, Yicong Li, Xiaokang Chen, Yuxi Liu, Taiping Han, Jiping Miao, Jun Fang, Qiang Cao, Yaming Tang, Yun Cui, Jie Xu, Wenyue Cui, Liwang Zhu, Jin Wong, Gary Li, Jian Jiang, Lubin Cell Discov Article Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites. JX21108 was developed from chemical optimization of quisinostat, a histone deacetylase inhibitor. We identified P. falciparum histone deacetylase 1 (PfHDAC1), an epigenetic regulator essential for parasite growth and invasion, as a molecular target of JX21108. PfHDAC1 knockdown leads to the downregulation of essential parasite genes, which is highly consistent with the transcriptomic changes induced by JX21108 treatment. Collectively, our data support that PfHDAC1 is a potential drug target for overcoming multidrug resistance and that JX21108 treats malaria and blocks parasite transmission simultaneously. Springer Singapore 2020-12-11 /pmc/articles/PMC7733455/ /pubmed/33311461 http://dx.doi.org/10.1038/s41421-020-00215-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| spellingShingle | Article Huang, Zhenghui Li, Ruoxi Tang, Tongke Ling, Dazheng Wang, Manjiong Xu, Dandan Sun, Maoxin Zheng, Lulu Zhu, Feng Min, Hui Boonhok, Rachasak Ding, Yan Wen, Yuhao Chen, Yicong Li, Xiaokang Chen, Yuxi Liu, Taiping Han, Jiping Miao, Jun Fang, Qiang Cao, Yaming Tang, Yun Cui, Jie Xu, Wenyue Cui, Liwang Zhu, Jin Wong, Gary Li, Jian Jiang, Lubin A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1 |
| title | A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1 |
| title_full | A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1 |
| title_fullStr | A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1 |
| title_full_unstemmed | A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1 |
| title_short | A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1 |
| title_sort | novel multistage antiplasmodial inhibitor targeting plasmodium falciparum histone deacetylase 1 |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733455/ https://www.ncbi.nlm.nih.gov/pubmed/33311461 http://dx.doi.org/10.1038/s41421-020-00215-4 |
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