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Nature Chemical Biology 4, 347–356 (1 June 2008) | doi:10.1038/nchembio.87

Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility

Nobutaka Kato , Tomoyo Sakata , Ghislain Breton , Karine G Le Roch , Advait Nagle , Carsten Andersen , Badry Bursulaya , Kerstin Henson , Jeffrey Johnson , Kota Arun Kumar , Felix Marr , Daniel Mason , Case McNamara , David Plouffe , Vandana Ramachandran , Muriel Spooner , Tove Tuntland , Yingyao Zhou , Eric C Peters , Arnab Chatterjee , Peter G Schultz , Gary E Ward , Nathanael Gray , Jeffrey Harper & Elizabeth A Winzeler

Calcium-dependent protein kinases play a crucial role in intracellular calcium signaling in plants, some algae and protozoa. In Plasmodium falciparum, calcium-dependent protein kinase 1 (PfCDPK1) is expressed during schizogony in the erythrocytic stage as well as in the sporozoite stage. It is coexpressed with genes that encode the parasite motor complex, a cellular component required for parasite invasion of host cells, parasite motility and potentially cytokinesis. A targeted gene-disruption approach demonstrated that pfcdpk1 seems to be essential for parasite viability. An in vitro biochemical screen using recombinant PfCDPK1 against a library of 20,000 compounds resulted in the identification of a series of structurally related 2,6,9-trisubstituted purines. Compound treatment caused sudden developmental arrest at the late schizont stage in P. falciparum and a large reduction in intracellular parasites in Toxoplasma gondii, which suggests a possible role for PfCDPK1 in regulation of parasite motility during egress and invasion.