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

• Published in: The Journal of infectious diseases Vol. 214; no. 12; pp. 1856 - 1864
• Main Authors: Schaefer, Deborah A., Betzer, Dana P., Smith, Kylie D., Millman, Zachary G., Michalski, Hannah C., Menchaca, Sarah E., Zambriski, Jennifer A., Ojo, Kayode K., Hulverson, Matthew A., Arnold, Samuel L. M., Rivas, Kasey L., Vidadala, Rama S. R., Huang, Wenlin, Barrett, Lynn K., Maly, Dustin J., Fan, Erkang, Van Voorhis, Wesley C., Riggs, Michael W.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 15.12.2016
• Subjects: Animals; Animals, Newborn; Antiprotozoal Agents - administration & dosage; Antiprotozoal Agents - adverse effects; Cattle; Cattle Diseases - drug therapy; Cryptosporidiosis - drug therapy; Cryptosporidium parvum - drug effects; Disease Models, Animal; Drug Evaluation, Preclinical; Major and Brief Reports; Mice, Inbred BALB C; PARASITES; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Treatment Outcome; therapeutic; Cryptosporidium; oocyst shedding; CpCDPK-1; animal model; clinical evaluation; cryptosporidiosis; bumped kinase inhibitor
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiw488

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.