A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis.
A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis.
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DOI：
10.1038/nature22337
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发表时间：
2017-06-15
期刊：
影响因子：
64.8
通讯作者：
Diagana TT
中科院分区：
文献类型：
--
作者：
Manjunatha UH;Vinayak S;Zambriski JA;Chao AT;Sy T;Noble CG;Bonamy GMC;Kondreddi RR;Zou B;Gedeck P;Brooks CF;Herbert GT;Sateriale A;Tandel J;Noh S;Lakshminarayana SB;Lim SH;Goodman LB;Bodenreider C;Feng G;Zhang L;Blasco F;Wagner J;Leong FJ;Striepen B;Diagana TT
腹泻病占全球儿童死亡率的8.6%。最近的流行病学研究发现，原生动物寄生虫隐孢子虫是儿童腹泻的主要原因，对婴儿和免疫功能低下的个体具有特别严重的影响。目前既没有疫苗，也没有有效的治疗方法。在这里，我们建立了一个药物发现过程，建立在可扩展的表型分析和小鼠模型，利用转基因寄生虫。通过筛选具有抗寄生虫活性的化合物，我们鉴定出吡唑吡啶类化合物是细小隐孢子虫和人隐孢子虫的抑制剂。口服吡唑吡啶KDU731可有效减少免疫功能低下小鼠的肠道感染。治疗还能迅速解决新生儿的腹泻和脱水问题，这是隐孢子虫病的一种临床模式，与人类感染非常相似。我们的研究结果表明，隐孢子虫脂质激酶PI(4)K（磷脂酰肌醇-4- oh激酶）是吡唑啉的靶点，KDU731作为治疗隐孢子虫病的候选药物值得进一步的临床前评估。本文的在线版本（doi:10.1038/nature22337）包含补充材料，可供授权用户使用。建立隐孢子虫病药物发现筛选管道，并鉴定吡唑吡啶作为隐孢子虫脂质激酶PI(4)K的选择性atp竞争性抑制剂。本文的在线版本（doi:10.1038/nature22337）包含补充材料，可供授权用户使用。隐孢子虫顶复合体寄生虫是小儿腹泻的主要原因，在婴儿和免疫系统较弱的个体中具有很高的死亡率。在这里，作者报告了隐孢子虫病药物发现筛选管道的建立，并确定吡唑吡啶是隐孢子虫脂质激酶PI(4)K的选择性atp竞争性抑制剂。主要候选药物KDU731在体外抑制小弧菌和人源弧菌的生长，并在免疫功能低下的小鼠和新生牛犊（一种人类疾病的临床模型）中显示出体内疗效。此外，KDU731满足广泛的安全性和药理学标准，并有潜力作为治疗隐孢子虫病急需的治疗药物。本文的在线版本（doi:10.1038/nature22337）包含补充材料，可供授权用户使用。
Diarrhoeal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of paediatric diarrhoea, with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor an effective treatment. Here we establish a drug discovery process built on scalable phenotypic assays and mouse models that take advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity, we identify pyrazolopyridines as inhibitors of Cryptosporidium parvum and Cryptosporidium hominis. Oral treatment with the pyrazolopyridine KDU731 results in a potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhoea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest that the Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) is a target for pyrazolopyridines and that KDU731 warrants further preclinical evaluation as a drug candidate for the treatment of cryptosporidiosis. The online version of this article (doi:10.1038/nature22337) contains supplementary material, which is available to authorized users. The establishment of a drug-discovery screening pipeline for cryptosporidiosis, and identification of pyrazolopyridines as selective ATP-competitive inhibitors of the Cryptosporidium lipid kinase PI(4)K. The online version of this article (doi:10.1038/nature22337) contains supplementary material, which is available to authorized users. The apicomplexan parasite Cryptosporidium is a leading cause of paediatric diarrhoea, with high mortality in infants and individuals with weak immune systems. Here, the authors report the establishment of a drug discovery screening pipeline for cryptosporidiosis, and identify pyrazolopyridines as selective ATP-competitive inhibitors of the Cryptosporidium lipid kinase PI(4)K. The lead candidate, KDU731, inhibits growth of C. parvum and C. hominis in vitro, and demonstrated in vivo efficacy in immunocompromised mice and neonatal calves (a clinical model of human disease). Moreover, KDU731 meets a broad range of safety and pharmacology criteria, and has potential as a much-needed therapeutic for treatment of cryptosporidiosis. The online version of this article (doi:10.1038/nature22337) contains supplementary material, which is available to authorized users.