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

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 () and Thierry T. Diagana ()
Additional contact information
Ujjini H. Manjunatha: Novartis Institute for Tropical Diseases
Sumiti Vinayak: Center for Tropical and Emerging Global Diseases, University of Georgia
Jennifer A. Zambriski: Washington State University, College of Veterinary Medicine, Paul G. Allen School for Global Animal Health
Alexander T. Chao: Novartis Institute for Tropical Diseases
Tracy Sy: Washington State University, College of Veterinary Medicine, Paul G. Allen School for Global Animal Health
Christian G. Noble: Novartis Institute for Tropical Diseases
Ghislain M. C. Bonamy: Novartis Institute for Tropical Diseases
Ravinder R. Kondreddi: Novartis Institute for Tropical Diseases
Bin Zou: Novartis Institute for Tropical Diseases
Peter Gedeck: Novartis Institute for Tropical Diseases
Carrie F. Brooks: Center for Tropical and Emerging Global Diseases, University of Georgia
Gillian T. Herbert: Center for Tropical and Emerging Global Diseases, University of Georgia
Adam Sateriale: Center for Tropical and Emerging Global Diseases, University of Georgia
Jayesh Tandel: University of Georgia
Susan Noh: Washington State University, College of Veterinary Medicine, Paul G. Allen School for Global Animal Health
Suresh B. Lakshminarayana: Novartis Institute for Tropical Diseases
Siau H. Lim: Novartis Institute for Tropical Diseases
Laura B. Goodman: Cornell University, College of Veterinary Medicine
Christophe Bodenreider: Novartis Institute for Tropical Diseases
Gu Feng: Novartis Institute for Tropical Diseases
Lijun Zhang: China Novartis Institutes for Biomedical Research, Zhangjiang Hi-Tech Park, Pudong
Francesca Blasco: Novartis Institute for Tropical Diseases
Juergen Wagner: Novartis Institute for Tropical Diseases
F. Joel Leong: Novartis Institute for Tropical Diseases
Boris Striepen: Center for Tropical and Emerging Global Diseases, University of Georgia
Thierry T. Diagana: Novartis Institute for Tropical Diseases

Nature, 2017, vol. 546, issue 7658, 376-380

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22337

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