A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis
| Autor: | Thierry T. Diagana, Suresh B. Lakshminarayana, Susan Noh, Francesca Blasco, Carrie F. Brooks, Jennifer A. Zambriski, Laura B. Goodman, Gu Feng, Sumiti Vinayak, Gillian T. Herbert, Peter Gedeck, Lijun Zhang, Jayesh Tandel, Siau H. Lim, Christian G. Noble, F. Joel Leong, Alex Chao, Juergen Wagner, Bin Zou, Boris Striepen, Tracy Sy, Ravinder Reddy Kondreddi, Christophe Bodenreider, Ujjini H. Manjunatha, Ghislain M. C. Bonamy, Adam Sateriale |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Pyridines Cryptosporidiosis Cryptosporidium Communicable Diseases Article Microbiology 03 medical and health sciences Immunocompromised Host Interferon-gamma Mice Cell Line Tumor parasitic diseases Pyrazolopyridine medicine Animals Humans Interferon gamma Rats Wistar 1-Phosphatidylinositol 4-Kinase Mice Knockout Multidisciplinary biology Kinase Drug discovery business.industry biology.organism_classification Antiparasitic agent Virology 3. Good health Rats Disease Models Animal 030104 developmental biology Cryptosporidium parvum Animals Newborn Pyrazoles Cattle Female business Cryptosporidium hominis medicine.drug |
| Zdroj: | Nature |
| ISSN: | 1476-4687 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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