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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.
Afiliação
  • Huang Z; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. zhhuang@ips.ac.cn.
  • Li R; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Tang T; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Ling D; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • Wang M; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Xu D; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Sun M; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Zheng L; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Zhu F; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Min H; Department of Microbiology and Parasitology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity, Bengbu, Anhui 233030, China.
  • Boonhok R; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • Ding Y; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Wen Y; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Chen Y; Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
  • Li X; Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
  • Chen Y; Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
  • Liu T; Department of Pathogenic Biology, Army Medical University, Chongqing 400038, China.
  • Han J; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • Miao J; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • Fang Q; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Cao Y; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Tang Y; Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110122, China.
  • Cui J; Department of Pathogenic Biology, Army Medical University, Chongqing 400038, China.
  • Xu W; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • Cui L; Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
  • Zhu J; Department of Microbiology and Parasitology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity, Bengbu, Anhui 233030, China.
  • Wong G; Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110122, China.
  • Li J; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • Jiang L; Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Cell Discov ; 6(1): 93, 2020 Dec 11.
Article em En | MEDLINE | ID: mdl-33311461
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article