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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
We thank S. Tzipori and D. Girouard for C. hominis oocysts; B. Nare for screening; B. H. Lee and J. Selva for high-content imaging data; M. Weaver for rat toxicology studies; I. Mueller for monkey pharmacokinetics; B. Yeung, O. Simon, J. Roland, V. Bollu, A. Chatterjee, A. Nagle, R. Moreau, and P. K. Mishra for compound synthesis; other Novartis Institutes for Biomedical Research (NIBR) colleagues for profiling; J. Burrows and K. Chibale for MMV390048; and M. Meissner for a plasmid carrying the red-shifted Fluc gene. This work was supported in part by the NIBR, the Wellcome Trust (Pathfinder 107678/Z/15/Z to B.S. and U.H.M.), and the National Institutes of Health (NIH R01AI112427 to B.S.). Inhibitors of the Plasmodium PI4K were discovered with the support of translational grants (WT078285 and WT096157) from the Wellcome Trust and funding from the Medicines for Malaria Venture (M.M.V.). B.S. is a Georgia Research Alliance Distinguished Investigator and A.S. is supported by NIH Fellowship F32AI124518. We thank our colleagues from Novartis Institute for Tropical Diseases, University of Georgia, Athens, Washington State University’s Office of the Campus Veterinarian, Animal Resource Unit, and the Office of Research Support and Operations and R. Anderson, 5D Dairy Farm, for their support. We are also grateful to the animal science and veterinary students at Washington State University for their participation in data collection and care of the research calves.
Extended data figures
This file contains further details on assembly and screening of NITD parasite box and calf efficacy study and Supplementary Table 1.
About this article
Nature Reviews Gastroenterology & Hepatology (2017)