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

Steven 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

67 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Toxoplasma
Protein Kinase Inhibitors
Parasites
Toxoplasmosis
Glycine
Phosphotransferases
Adenosine Triphosphate
Cell Line
Health
Enzymes
Growth
calcium-dependent protein kinase
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Development of Toxoplasma gondii calcium-dependent protein kinase 1 (Tg CDPK1) inhibitors with potent anti- toxoplasma activity. / Johnson, Steven; Murphy, Ryan C.; Geiger, Jennifer A.; Derocher, Amy E.; Zhang, Zhongsheng; Ojo, Kayode K.; Larson, Eric T.; Perera, B. Gayani K; Dale, Edward J.; He, Panqing; Reid, Molly C.; Fox, Anna M W; Mueller, Natascha R.; Merritt, Ethan A.; Fan, Erkang; Parsons, Marilyn; Van Voorhis, Wesley C.; Maly, Dustin J.

In: Journal of Medicinal Chemistry, Vol. 55, No. 5, 08.03.2012, p. 2416-2426.

Research output: Contribution to journalArticle

Johnson, S, Murphy, RC, Geiger, JA, Derocher, AE, Zhang, Z, Ojo, KK, Larson, ET, Perera, BGK, Dale, EJ, He, P, Reid, MC, Fox, AMW, Mueller, NR, Merritt, EA, Fan, E, Parsons, M, Van Voorhis, WC & Maly, DJ 2012, 'Development of Toxoplasma gondii calcium-dependent protein kinase 1 (Tg CDPK1) inhibitors with potent anti- toxoplasma activity', Journal of Medicinal Chemistry, vol. 55, no. 5, pp. 2416-2426. https://doi.org/10.1021/jm201713h
Johnson, Steven ; Murphy, Ryan C. ; Geiger, Jennifer A. ; Derocher, Amy E. ; Zhang, Zhongsheng ; Ojo, Kayode K. ; Larson, Eric T. ; Perera, B. Gayani K ; Dale, Edward J. ; He, Panqing ; Reid, Molly C. ; Fox, Anna M W ; Mueller, Natascha R. ; Merritt, Ethan A. ; Fan, Erkang ; Parsons, Marilyn ; Van Voorhis, Wesley C. ; Maly, Dustin J. / Development of Toxoplasma gondii calcium-dependent protein kinase 1 (Tg CDPK1) inhibitors with potent anti- toxoplasma activity. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 5. pp. 2416-2426.
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