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

• Published in: Nature (London) Vol. 546; no. 7658; pp. 376 - 380
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 15.06.2017; Nature Publishing Group UK
• Subjects: 1-Phosphatidylinositol 4-Kinase - antagonists & inhibitors; Animal models; Animals; Animals, Newborn; Calves; Cattle; Cell Line, Tumor; Cryptosporidiosis; Cryptosporidiosis - drug therapy; Cryptosporidiosis - parasitology; Cryptosporidium; Cryptosporidium - drug effects; Cryptosporidium - enzymology; Cryptosporidium parvum; Dehydration; Diarrhea; Disease Models, Animal; Drug discovery; Epidemiology; Female; Humans; Immunocompromised Host; Infants; Infections; Interferon-gamma - deficiency; Interferon-gamma - genetics; Intestine; Kinases; Libraries; Lipid kinase; Male; Mice; Mice, Knockout; Neonates; Parasites; Parasitic diseases; Protozoa; Pyrazoles - chemistry; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Rats, Wistar
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature22337

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.