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

  • Nature. 2017 Jun 15;546(7658):376-380. doi: 10.1038/nature22337.
Ujjini H Manjunatha   #  1 ,  Sumiti Vinayak   #  2 ,  Jennifer A Zambriski   #  3 ,  Alexander T Chao  1 ,  Tracy Sy  3 ,  Christian G Noble  1 ,  Ghislain M C Bonamy  1 ,  Ravinder R Kondreddi  1 ,  Bin Zou  1 ,  Peter Gedeck  1 ,  Carrie F Brooks  2 ,  Gillian T Herbert  2 ,  Adam Sateriale  2 ,  Jayesh Tandel  4 ,  Susan Noh  3  5 ,  Suresh B Lakshminarayana  1 ,  Siau H Lim  1 ,  Laura B Goodman  6 ,  Christophe Bodenreider  1 ,  Gu Feng  1 ,  Lijun Zhang  7 ,  Francesca Blasco  1 ,  Juergen Wagner  1 ,  F Joel Leong  1 ,  Boris Striepen  2  4 ,  Thierry T Diagana  1
Affiliations
  • 1. Novartis Institute for Tropical Diseases, Singapore 138670.
  • 2. Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA.
  • 3. Washington State University, College of Veterinary Medicine, Paul G. Allen School for Global Animal Health, Pullman, WA, USA.
  • 4. Department of Cellular Biology, University of Georgia, Athens, GA, USA.
  • 5. USDA-Agricultural Research Service, Animal Disease Research Unit and Washington State University, Department of Veterinary Microbiology and Pathology, Washington Animal Disease Diagnostic Laboratory, Pullman, WA, USA.
  • 6. Cornell University, College of Veterinary Medicine, Department of Population Medicine and Diagnostic Sciences, Ithaca, NY, USA.
  • 7. China Novartis Institute for Biomedical Research, Shanghai 201203, China.
  • # Contributed equally.
PMID: 28562588 DOI: 10.1038/nature22337
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.

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