A novel calcium-dependent protein kinase inhibitor as a lead compound for treating cryptosporidiosis

Alejandro Castellanos-Gonzalez, A. Clinton White, Kayode K. Ojo, Rama S.R. Vidadala, Zhongsheng Zhang, Molly C. Reid, Anna M.W. Fox, Katelyn R. Keyloun, Kasey Rivas, Ayesha Irani, Sara M. Dann, Erkang Fan, Dustin J. Maly, Wesley C. Van Voorhis

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Cryptosporidium parasites infect intestinal cells, causing cryptosporidiosis. Despite its high morbidity and association with stunting in the developing world, current therapies for cryptosporidiosis have limited efficacy. Calcium-dependent protein kinases (CDPKs) are essential enzymes in the biology of protozoan parasites. CDPK1 was cloned from the genome of Cryptosporidium parvum, and potent and specific inhibitors have been developed based on structural studies. In this study, we evaluated the anti-Cryptosporidium activity of a novel CDPK1 inhibitor, 1294, and demonstrated that 1294 significantly reduces parasite infection in vitro, with a half maximal effective concentration of 100 nM. Pharmacokinetic studies revealed that 1294 is well absorbed, with a half-life supporting daily administration. Oral therapy with 1294 eliminated Cryptosporidium parasites from 6 of 7 infected severe combined immunodeficiency-beige mice, and the parasites did not recur in these immunosuppressed mice. Mice treated with 1294 had less epithelial damage, corresponding to less apoptosis. Thus, 1294 is an important lead for the development of drugs for treatment of cryptosporidiosis.

Original languageEnglish (US)
Pages (from-to)1342-1348
Number of pages7
JournalJournal of Infectious Diseases
Volume208
Issue number8
DOIs
StatePublished - Oct 15 2013

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Keywords

  • Calcium-dependant Protein kinase
  • CpCDPK-1
  • Cryptosporidium parvum
  • antiparasitic
  • bumped kinase inhibitor
  • cryptosporidiosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Castellanos-Gonzalez, A., White, A. C., Ojo, K. K., Vidadala, R. S. R., Zhang, Z., Reid, M. C., Fox, A. M. W., Keyloun, K. R., Rivas, K., Irani, A., Dann, S. M., Fan, E., Maly, D. J., & Van Voorhis, W. C. (2013). A novel calcium-dependent protein kinase inhibitor as a lead compound for treating cryptosporidiosis. Journal of Infectious Diseases, 208(8), 1342-1348. https://doi.org/10.1093/infdis/jit327