文献类型：期刊文献

英文题名：A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1

作者：Huang, Zhenghui[1];Li, Ruoxi[2,3];Tang, Tongke[1,4];Ling, Dazheng[2,3];Wang, Manjiong[2,3];Xu, Dandan[5,6];Sun, Maoxin[1,4];Zheng, Lulu[3];Zhu, Feng[7];Min, Hui[7];Boonhok, Rachasak[7];Ding, Yan[8];Wen, Yuhao[1];Chen, Yicong[1];Li, Xiaokang[2,3];Chen, Yuxi[9];Liu, Taiping[8];Han, Jiping[1];Miao, Jun[7];Fang, Qiang[5,6];Cao, Yaming[9];Tang, Yun[3];Cui, Jie[1];Xu, Wenyue[8];Cui, Liwang[7];Zhu, Jin[2,3];Wong, Gary[1];Li, Jian[2,3];Jiang, Lubin[1,4]

机构：[1]Univ Chinese Acad Sci, Chinese Acad Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China;[2]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[3]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[4]ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;[5]Bengbu Med Coll, Dept Microbiol & Parasitol, Bengbu 233030, Anhui, Peoples R China;[6]Anhui Key Lab Infect & Immun, Bengbu 233030, Anhui, Peoples R China;[7]Univ S Florida, Div Infect Dis & Int Med, Dept Internal Med, Morsani Coll Med, Tampa, FL 33620 USA;[8]Army Med Univ, Dept Pathogen Biol, Chongqing 400038, Peoples R China;[9]China Med Univ, Coll Basic Med Sci, Dept Immunol, Shenyang 110122, Liaoning, Peoples R China

年份：2020

卷号：6

期号：1

外文期刊名：CELL DISCOVERY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000598238100001)】；

基金：We thank Dr. Didier Menard for providing the artemisinin-resistant field isolates. This research was supported by the National Key R&D Program of China (2018YFA0507300), the Innovative Research Team of High-level Local Universities in Shanghai, and the National Special Fund for State Key Laboratory of Bioreactor Engineering (2060204), the National Science and Technology Major Project (2018ZX10101004003001), the National Natural Science Foundation of China (31571345, 31771455, 81772218), Pu'er Municipal Expert Workstation of L. J. and National Institute of Allergy and Infectious Diseases Grants R01AI116466 and U19AI089672.

语种：英文

摘要：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.