A novel calcium-dependent kinase inhibitor, bumped kinase inhibitor 1517, cures cryptosporidiosis in immunosuppressed mice

Alejandro Castellanos, Hayley Sparks, Samantha Nava, Wenlin Huang, Zhongsheng Zhang, Kasey Rivas, Matthew A. Hulverson, Lynn K. Barrett, Kayode K. Ojo, Erkang Fan, Wesley C. Van Voorhis, A. Clinton White

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Cryptosporidium is recognized as one of the main causes of childhood diarrhea worldwide. However, the current treatment for cryptosporidiosis is suboptimal. Calcium flux is essential for entry in apicomplexan parasites. Calcium-dependent protein kinases (CDPKs) are distinct from protein kinases of mammals, and the CDPK1 of the apicomplexan Cryptosporidium lack side chains that typically block a hydrophobic pocket in protein kinases. We exploited this to develop bumped kinase inhibitors (BKIs) that selectively target CDPK1. We have shown that several BKIs of Cryptosporidium CDPK1 potently reduce enzymatic activity and decrease parasite numbers when tested in vitro. In the present work, we studied the anticryptosporidial activity of BKI-1517, a novel BKI. The half maximal effective concentration for Cryptosporidium parvum in HCT-8 cells was determined to be approximately 50 nM. Silencing experiments of CDPK1 suggest that BKI-1517 acts on CDPK1 as its primary target. In a mouse model of chronic infection, 5 of 6 SCID/beige mice (83.3%) were cured after treatment with a single daily dose of 120 mg/kg BKI-1517. No side effects were observed. These data support advancing BKI-1517 as a lead compound for drug development for cryptosporidiosis.

Original languageEnglish (US)
Pages (from-to)1850-1855
Number of pages6
JournalJournal of Infectious Diseases
Volume214
Issue number12
DOIs
StatePublished - Dec 1 2016

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Keywords

  • BKI
  • CDPK
  • CDPK1
  • Cryptosporidiosis
  • Cryptosporidium
  • Kinase inhibitors
  • SiRNA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Castellanos, A., Sparks, H., Nava, S., Huang, W., Zhang, Z., Rivas, K., Hulverson, M. A., Barrett, L. K., Ojo, K. K., Fan, E., Van Voorhis, W. C., & White, A. C. (2016). A novel calcium-dependent kinase inhibitor, bumped kinase inhibitor 1517, cures cryptosporidiosis in immunosuppressed mice. Journal of Infectious Diseases, 214(12), 1850-1855. https://doi.org/10.1093/infdis/jiw481