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

2010; American Chemical Society; Volume: 1; Issue: 7 Linguagem: Inglês

10.1021/ml100096t

1948-5875

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

Signaling Pathways in Disease

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.