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Chemical genetics of Plasmodium falciparum

机译:恶性疟原虫的化学遗传学

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摘要

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.
机译:恶性疟原虫引起的疟疾是一种疾病,全世界每年造成880,000人死亡。事实证明,开发疫苗很困难,并且大多数抗疟疾药物已产生耐药性。为了发现新的抗疟药化学型,我们使用了表型正向化学遗传方法来测定309,474种化学物质。在这里,我们公开了整个文库的结构和生物学活性,其中许多文库显示了针对耐药性恶性疟原虫菌株的有效体外活性,并详细分析了172个代表性候选药物。一项反向化学遗传研究确定了61种疟疾蛋白中的19种新抑制剂和4种经过验证的药物靶标,以及15种新型结合剂。几种生物的植物化学发生谱显示,弓形虫与哺乳动物细胞系相似,恶性疟原虫与相关原生动物之间也相似。一种示例性化合物在鼠模型中显示功效。我们的发现为科学界提供了疟疾药物发现的新起点。

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  • 来源
    《Nature》 |2010年第7296期|p.311-315|共5页
  • 作者单位

    Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane 4111, Australia;

    Department of Medicine, University of Washington, Seattle, Washington 98195-7185, USA;

    Department of Biology and the Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World, Tres Cantos 28760, Spain;

    GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World, Tres Cantos 28760, Spain;

    Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2542, USA;

    W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA;

    Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA;

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA;

    Medicines for Malaria Venture, Geneva 1215, Switzerland;

    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA;

    Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA;

    Experimental Chemotherapy Lab, Portland VA Medical Center, Portland, Oregon 97239, USA;

    Department of Chemistry and Chemical Biology Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA;

    Department of Chemistry and Chemical Biology Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA;

    GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World, Tres Cantos 28760, Spain;

    GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World, Tres Cantos 28760, Spain;

    Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA;

    Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2542, USA;

    W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA;

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA;

    Department of Biology and the Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Experimental Chemotherapy Lab, Portland VA Medical Center, Portland, Oregon 97239, USA;

    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA;

    Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA;

    Department of Medicine, University of Washington, Seattle, Washington 98195-7185, USA;

    Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane 4111, Australia;

    Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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