Bumped-kinase inhibitors for cryptosporidiosis therapy

Matthew A. Hulverson, Sumiti Vinayak, Ryan Choi, Deborah A. Schaefer, Alejandro Castellanos-Gonzalez, Rama S.R. Vidadala, Carrie F. Brooks, Gillian T. Herbert, Dana P. Betzer, Grant R. Whitman, Hayley N. Sparks, Samuel L.M. Arnold, Kasey L. Rivas, Lynn K. Barrett, A. Clinton White, Dustin J. Maly, Michael W Riggs, Boris Striepen, Wesley C. Van Voorhis, Kayode K. Ojo

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Bumped kinase inhibitors (BKIs) of Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) are leading candidates for treatment of cryptosporidiosis-associated diarrhea. Potential cardiotoxicity related to anti–human ether-à-go-go potassium channel (hERG) activity of the first-generation anti-Cryptosporidium BKIs triggered further testing for efficacy. A luminescence assay adapted for high-throughput screening was used to measure inhibitory activities of BKIs against C. parvum in vitro. Furthermore, neonatal and interferon γ knockout mouse models of C. parvum infection identified BKIs with in vivo activity. Additional iterative experiments for optimum dosing and selecting BKIs with minimum levels of hERG activity and frequencies of other safety liabilities included those that investigated mammalian cell cytotoxicity, C. parvum proliferation inhibition in vitro, anti–human Src inhibition, hERG activity, in vivo pharmacokinetic data, and efficacy in other mouse models. Findings of this study suggest that fecal concentrations greater than parasite inhibitory concentrations correlate best with effective therapy in the mouse model of cryptosporidiosis, but a more refined model for efficacy is needed.

Original languageEnglish (US)
Pages (from-to)1275-1284
Number of pages10
JournalJournal of Infectious Diseases
Volume215
Issue number8
DOIs
StatePublished - 2017

Keywords

  • Bumped kinase inhibitors
  • Calcium-dependent protein kinase 1
  • Cryptosporidiosis treatment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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  • Cite this

    Hulverson, M. A., Vinayak, S., Choi, R., Schaefer, D. A., Castellanos-Gonzalez, A., Vidadala, R. S. R., Brooks, C. F., Herbert, G. T., Betzer, D. P., Whitman, G. R., Sparks, H. N., Arnold, S. L. M., Rivas, K. L., Barrett, L. K., White, A. C., Maly, D. J., Riggs, M. W., Striepen, B., Van Voorhis, W. C., & Ojo, K. K. (2017). Bumped-kinase inhibitors for cryptosporidiosis therapy. Journal of Infectious Diseases, 215(8), 1275-1284. https://doi.org/10.1093/infdis/jix120