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

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

Nature (2017-06-01)
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
摘要

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.