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

5 years ago

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

Adam Sateriale, Ravinder R. Kondreddi, Peter Gedeck, Christian G. Noble, Carrie F. Brooks, Sumiti Vinayak, Francesca Blasco, Laura B. Goodman, Siau H. Lim, Suresh B. Lakshminarayana, Lijun Zhang, Tracy Sy, Thierry T. Diagana, Boris Striepen, Bin Zou, Ghislain M. C. Bonamy, Jayesh Tandel, F. Joel Leong, Gu Feng, Susan Noh, Ujjini H. Manjunatha, Christophe Bodenreider, Alexander T. Chao, Juergen Wagner, Gillian T. Herbert, Jennifer A. Zambriski

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.

Publisher URL: http://dx.doi.org/10.1038/nature22337

DOI: 10.1038/nature22337