2. Academic Validation
  3. 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 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

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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