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Manjunatha, Ujjini H; Vinayak, Sumiti; Zambriski, Jennifer A; Chao, Alexander T; Sy, Tracy; Noble, Christian G; Bonamy, Ghislain M C; Kondreddi, Ravinder R; Zou, Bin; Gedeck, Peter; Brooks, Carrie F; Herbert, Gillian T; Sateriale, Adam; Tandel, Jayesh; Noh, Susan; Lakshminarayana, Suresh B; Lim, Siau H; Goodman, Laura B; Bodenreider, Christophe; Feng, Gu; Zhang, Lijun; Blasco, Francesca; Wagner, Juergen; Leong, F Joel; Striepen, Boris; Diagana, Thierry T
Nature (London), 06/2017, Letnik: 546, Številka: 7658Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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