Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity

J Med Chem. 2012 Feb 9. [Epub ahead of print]

Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity.

Johnson SM, Murphy RC, Geiger JA, Derocher A, Zhang Z, Ojo K, Larson E, Perera BG, Dale E, He P, Fox A, Mueller N, Merritt EA, Fan E, Reid M, Parsons M, Van Voorhis WC, Maly DJ.

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.

PMID: 22320388 [PubMed - as supplied by publisher]