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J Infect Dis. 2016 Dec 15;214(12):1856-1864. Epub 2016 Oct 17.

Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis.

Author information

1
School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
2
Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University, Pullman.
3
Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease.
4
Department of Chemistry.
5
Department of Biochemistry, University of Washington, Seattle.

Abstract

Cryptosporidiosis, caused by the apicomplexan parasite Cryptosporidium parvum, is a diarrheal disease that has produced a large global burden in mortality and morbidity in humans and livestock. There are currently no consistently effective parasite-specific pharmaceuticals available for this disease. Bumped kinase inhibitors (BKIs) specific for parasite calcium-dependent protein kinases (CDPKs) have been shown to reduce infection in several parasites having medical and veterinary importance, including Toxoplasma gondii, Plasmodium falciparum, and C. parvum In the present study, BKIs were screened for efficacy against C. parvum infection in the neonatal mouse model. Three BKIs were then selected for safety and clinical efficacy evaluation in the calf model for cryptosporidiosis. Significant BKI treatment effects were observed for virtually all clinical and parasitological scoring parameters, including diarrhea severity, oocyst shedding, and overall health. These results provide proof of concept for BKIs as therapeutic drug leads in an animal model for human cryptosporidiosis.

KEYWORDS:

CpCDPK-1; Cryptosporidium; animal model; bumped kinase inhibitor; clinical evaluation; cryptosporidiosis; oocyst shedding; therapeutic

PMID:
27923949
PMCID:
PMC5142098
DOI:
10.1093/infdis/jiw488
[Indexed for MEDLINE]
Free PMC Article

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