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

Abstract

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.

• Authors: Ujjini H Manjunatha, Sumiti Vinayak, Jennifer A Zambriski, Alexander T Chao, Tracy Sy, Christian G Noble, Ghislain M C Bonamy, Ravinder R Kondreddi, Bin Zou, Peter Gedeck, Carrie F Brooks, Gillian T Herbert, Adam Sateriale, Jayesh Tandel, Susan Noh, Suresh B Lakshminarayana, Siau H Lim, Laura B Goodman, Christophe Bodenreider, Gu Feng, Lijun Zhang, Francesca Blasco, Juergen Wagner, F Joel Leong, Boris Striepen, Thierry T Diagana
• Journal: Nature (Nature) Vol. 546 Issue 7658 Pg. 376-380 (06 15 2017) ISSN: 1476-4687 [Electronic] England
• PMID: 28562588 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• KDU731
• Pyrazoles
• Pyridines
• pyrazolopyridine
• Interferon-gamma
• 1-Phosphatidylinositol 4-Kinase

Topics

• 1-Phosphatidylinositol 4-Kinase (antagonists & inhibitors)
• Animals
• Animals, Newborn
• Cattle
• Cell Line, Tumor
• Cryptosporidiosis (drug therapy, parasitology)
• Cryptosporidium (drug effects, enzymology)
• Disease Models, Animal
• Female
• Humans
• Immunocompromised Host
• Interferon-gamma (deficiency, genetics)
• Male
• Mice
• Mice, Knockout
• Pyrazoles (chemistry, pharmacokinetics, pharmacology)
• Pyridines (chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Wistar