Discovery of Potent and Selective Inhibitors of CDPK1 from C. parvum and T. gondii

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...

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Published inACS medicinal chemistry letters Vol. 1; no. 7; pp. 331 - 335
Main Authors Murphy, Ryan C, Ojo, Kayode K, Larson, Eric T, Castellanos-Gonzalez, Alejandro, Perera, B. Gayani K, Keyloun, Katelyn R, Kim, Jessica E, Bhandari, Janhavi G, Muller, Natascha R, Verlinde, Christophe L. M. J, White, A. Clinton, Merritt, Ethan A, Van Voorhis, Wesley C, Maly, Dustin J
Format Journal Article
LanguageEnglish
Published American Chemical Society 14.10.2010
Subjects
Letter
Phosphorylation
Toxoplasma gondii
Cryptosporidium parvum
protozoans
apicomplexan
calcium-dependent protein kinases
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Summary: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.
Bibliography:These authors contributed equally to the manuscript.
This work was funded by National Institute of Allergy and Infectious Diseases Grants R01AI080625 (W.C.V.V.) and R01AI067921 (C.L.M.J.V., E.A.M., and W.C.V.V.), National Institute of General Medical Sciences Grant R01GM086858 (D.J.M.), and financial support from G. and K. Pigotti.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml100096t