Development of Toxoplasma gondii calcium-dependent protein kinase 1 (Tg CDPK1) inhibitors with potent anti- toxoplasma activity

Steven M. Johnson, Ryan C. Murphy, Jennifer A. Geiger, Amy E. Derocher, Zhongsheng Zhang, Kayode K. Ojo, Eric T. Larson, B. Gayani K. Perera, Edward J. Dale, Panqing He, Molly C. Reid, Anna M.W. Fox, Natascha R. Mueller, Ethan A. Merritt, Erkang Fan, Marilyn Parsons, Wesley C. Van Voorhis, Dustin J. Maly

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.

Original languageEnglish (US)
Pages (from-to)2416-2426
Number of pages11
JournalJournal of Medicinal Chemistry
Volume55
Issue number5
DOIs
StatePublished - Mar 8 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Development of Toxoplasma gondii calcium-dependent protein kinase 1 (Tg CDPK1) inhibitors with potent anti- toxoplasma activity'. Together they form a unique fingerprint.

  • Cite this

    Johnson, S. M., Murphy, R. C., Geiger, J. A., Derocher, A. E., Zhang, Z., Ojo, K. K., Larson, E. T., Perera, B. G. K., Dale, E. J., He, P., Reid, M. C., Fox, A. M. W., Mueller, N. R., Merritt, E. A., Fan, E., Parsons, M., Van Voorhis, W. C., & Maly, D. J. (2012). Development of Toxoplasma gondii calcium-dependent protein kinase 1 (Tg CDPK1) inhibitors with potent anti- toxoplasma activity. Journal of Medicinal Chemistry, 55(5), 2416-2426. https://doi.org/10.1021/jm201713h