Discovery of potent and selective inhibitors of CDPK1 from C. parvum and T. gondii

Ryan C. Murphy, Kayode K. Ojo, Eric T. Larson, Alejandro Castellanos-Gonzalez, B. Gayani K. Perera, Katelyn R. Keyloun, Jessica E. Kim, Janhavi G. Bhandari, Natascha R. Muller, Christophe L.M.J. Verlinde, A. Clinton White, Ethan A. Merritt, Wesley C. Van Voorhis, Dustin J. Maly

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

The protozoans Cryptosporidium parvum and Toxoplasma gondii are parasites of major health concern to humans. Both parasites contain a group of calcium-dependent protein kinases (CDPKs) which are found in plants and ciliates but not in humans or fungi. Here, we describe a series of potent inhibitors that target CDPK1 in C. parvum (CpCDPK1) and T. gondii (TgCDPK1). These inhibitors are highly selective for CpCDPK1 and TgCDPK1 over the mammalian kinases SRC and ABL. Furthermore, they are able to block an early stage of C. parvum invasion of HCT-8 host cells, which is similar to their effects on T. gondii invasion of human fibroblasts.

Original languageEnglish (US)
Pages (from-to)331-335
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume1
Issue number7
DOIs
StatePublished - Oct 14 2010

Keywords

  • Cryptosporidium parvum
  • Phosphorylation
  • Toxoplasma gondii
  • apicomplexan
  • calcium-dependent protein kinases
  • protozoans

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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    Murphy, R. C., Ojo, K. K., Larson, E. T., Castellanos-Gonzalez, A., Perera, B. G. K., Keyloun, K. R., Kim, J. E., Bhandari, J. G., Muller, N. R., Verlinde, C. L. M. J., White, A. C., Merritt, E. A., Van Voorhis, W. C., & Maly, D. J. (2010). Discovery of potent and selective inhibitors of CDPK1 from C. parvum and T. gondii. ACS Medicinal Chemistry Letters, 1(7), 331-335. https://doi.org/10.1021/ml100096t