A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

Article

关键词: DEVELOPING-COUNTRIES;    ZAMBIAN CHILDREN;    PARVUM;    NITAZOXANIDE;    ANTIMALARIAL;    MORTALITY;    DIARRHEA;    BURDEN;    ASSAYS;    PCR;   

DOI  :  10.1038/nature22337

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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