A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis.
Nature
; 546(7658): 376-380, 2017 06 15.
Article
in En
| MEDLINE
| ID: mdl-28562588
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.
Full text:
1
Database:
MEDLINE
Main subject:
Pyrazoles
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Pyridines
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1-Phosphatidylinositol 4-Kinase
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Cryptosporidiosis
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Cryptosporidium
Limits:
Animals
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Female
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Humans
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Male
Language:
En
Journal:
Nature
Year:
2017
Type:
Article