Novel bumped kinase inhibitors are safe and effective therapeutics in the calf clinical model for cryptosporidiosis

Deborah A. Schaefer, Dana P. Betzer, Kylie D. Smith, Zachary G. Millman, Hannah C. Michalski, Sarah E. Menchaca, Jennifer A. Zambriski, Kayode K. Ojo, Matthew A. Hulverson, Samuel L M Arnold, Kasey L. Rivas, Rama S R Vidadala, Wenlin Huang, Lynn K. Barrett, Dustin J. Maly, Erkang Fan, Wesley C. Van Voorhis, Michael W Riggs

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1856-1864
Number of pages9
JournalJournal of Infectious Diseases
Volume214
Issue number12
DOIs
StatePublished - Dec 1 2016

Keywords

  • Animal model
  • Bumped kinase inhibitor
  • Clinical evaluation
  • CpCDPK-1
  • Cryptosporidiosis
  • Cryptosporidium
  • Oocyst shedding
  • Therapeutic

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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  • Cite this

    Schaefer, D. A., Betzer, D. P., Smith, K. D., Millman, Z. G., Michalski, H. C., Menchaca, S. E., Zambriski, J. A., Ojo, K. K., Hulverson, M. A., Arnold, S. L. M., Rivas, K. L., Vidadala, R. S. R., Huang, W., Barrett, L. K., Maly, D. J., Fan, E., Van Voorhis, W. C., & Riggs, M. W. (2016). Novel bumped kinase inhibitors are safe and effective therapeutics in the calf clinical model for cryptosporidiosis. Journal of Infectious Diseases, 214(12), 1856-1864. https://doi.org/10.1093/infdis/jiw488