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

  • Nat Chem Biol. 2008 Jun;4(6):347-56. doi: 10.1038/nchembio.87.
Nobutaka Kato  1 ,  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
Affiliations
  • 1. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND202 La Jolla, California 92037, USA.
PMID: 18454143 DOI: 10.1038/nchembio.87
Abstract

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.

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