Manjunatha, Ujjini Havaldar, Diagana, Thierry Tidiane, Vinayak, Sumiti, Zambriski, Jennifer, Striepen, Boris, Chao, Alexander, Noble, Christian Guy, Bonamy, Ghislain, Kondreddi, Ravinder Reddy, Zou, Bin, Gedeck, Peter, Lakshminarayana, Suresh Bangalore, Lim, Siau Hoi, Yeung, Bryan King Sing, Bodenreider, Christophe, Gu, Feng, Zhang, Lijun, Blasco, Francesca, Wagner, Juergen, Leong, Franz Joel Wen, Sy, Tracy, Noh, Susan, Goodman, Laura, Brooks, Carrie, Herbert, Gillian, Sateriale, Adam and Tandel, Jayesh (2017) A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis. Nature. ISSN 0028-08361476-4687

Abstract

The apicomplexan parasite Cryptosporidium is a major cause of infectious diarrhea in children and there are no consistently effective therapies to treat this disease. The search for cryptosporidiosis therapeutics has been hindered by the dearth of models amenable to modern drug discovery approaches. We established a cryptosporidiosis drug discovery screening process built on scalable phenotypic assays and a novel mouse model. We identified pyrazolopyridines as selective ATP-competitive inhibitors of the Cryptosporidium lipid kinase PI(4)K. The pyrazolopyridine KDU731 inhibits Cryptosporidium growth in multiple in vitro assays. In addition, oral treatment with KDU731 results in potent reduction in oocyst shedding in Cryptosporidium infected immunocompromised mice as well as rapid resolution of diarrheal symptoms in the neonatal calf cryptosporidiosis model. Collectively, our results chemically validate the Cryptosporidium lipid kinase PI(4)K as a drug target for the treatment of cryptosporidiosis and support the progression of the drug candidate KDU731 to further preclinical characterization.

Item Type:	Article
Date Deposited:	16 Jun 2017 00:45
Last Modified:	16 Jun 2017 00:45
URI:	https://oak.novartis.com/id/eprint/31278