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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis
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Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis

机译：内源性类喹诺酮类药物对急性和潜伏性弓形虫病非常有效

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摘要

Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors of T. gondii growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against T. gondii and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC_(50) values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED_(50) values of 0.14 mg/kg and 0.08 mg/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316 are highly active against the cyst form of T. gondii in mice at low doses, reducing cyst burden by 76-88% after 16 d of treatment. To investigate the ELQ mechanism of action against T. gondii, we demonstrate that endochin and ELQ-271 inhibit cytochrome c reduction by the T. gondii cytochrome bx_1, complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the Saccharomyces cerevisiae cytochrome be, complex, and an M221Q amino acid substitution in the Qi site of the protein leads to > 100-fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Qi site of the T. gondii cytochrome bc_1, complex.
机译：弓形虫是一种广泛分布的原生动物病原体，可导致毁灭性的眼部和中枢神经系统疾病。我们显示，类内啡肽样喹诺酮（ELQ）类化合物在体外含有弓形虫生长的极强抑制剂，并且对小鼠的急性和潜在弓形虫病有效。我们针对弓形虫筛选了50个ELQ，并选择了两种先导化合物E​​LQ-271和ELQ-316进行评估。 ELQ-271和ELQ-316的体外IC_（50）值分别为0.1 nM和0.007 nM。当对患有急性弓形虫病的小鼠口服时，ELQ-271和ELQ-316的ED_（50）值为0.14 mg / kg和0.08 mg / kg。此外，ELQ-271和ELQ-316在低剂量下对刚地弓形虫的囊肿形式具有高活性，在治疗16天后，囊肿负担减少了76-88％。为了研究ELQ对抗弓形虫的作用机理，我们证明了内啡肽和ELQ-271抑制弓形虫细胞色素bx_1的细胞色素c还原，复合物分别为8 nM和31 nM。我们还显示，ELQ-271抑制酿酒酵母细胞色素形成，复合物，并且蛋白质Qi部位的M221Q氨基酸取代导致抗性> 100倍。我们得出的结论是，ELQ-271和ELQ-316是口服生物可用药物，可有效对抗急性和潜伏弓形虫病，可能充当弓形虫细胞色素bc_1复杂Qi部位的抑制剂。

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    J. Stone Doggett; Aaron Nilsen; Isaac Forquer; Keith W. Wegtnann; Lorraine Jones-Brando; Robert H. Yolken; Claudia Bordon; Susan A. Charman; Kasiram Katneni; Tracey Schultz; Jeremy N. Burrows; David J. Hinrichs; Brigitte Meunier; Vern B. Carruthers; Michael K. Riscoe;

  • 作者单位

    Division of Infectious Diseases, Oregon Health and Science University, Portland, OR 97239,Veterans Administration Medical Center, Portland, OR 97239;

    Veterans Administration Medical Center, Portland, OR 97239;

    Veterans Administration Medical Center, Portland, OR 97239;

    Veterans Administration Medical Center, Portland, OR 97239;

    Stanley Division of Developmental Neurovirology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;

    Stanley Division of Developmental Neurovirology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;

    Stanley Division of Developmental Neurovirology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;

    Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia;

    Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia;

    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Ml 48109;

    Medicines for Malaria Venture, Geneva 15, Switzerland;

    Veterans Administration Medical Center, Portland, OR 97239;

    Centre de Genetique Moleculaire, Unite Propre de Recherche 3404, Centre National de la Recherche Scientifique, Gif-sur-Yvette 91198, France;

    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Ml 48109;

    Veterans Administration Medical Center, Portland, OR 97239,Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    antiparasitic agents; electron transport; antimalarial; quinoline; opportunistic infection;

    机译：抗寄生虫药;电子传输抗疟疾喹啉;机会感染;

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