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. Epub 2008 May 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry
  • Adenine / pharmacology
  • Adenine / therapeutic use
  • Animals
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • CHO Cells
  • Cell Line
  • Cell Proliferation / drug effects
  • Cricetinae
  • Cricetulus
  • Cyclohexylamines / chemistry
  • Cyclohexylamines / pharmacology*
  • Cyclohexylamines / therapeutic use
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics*
  • HeLa Cells
  • Humans
  • Life Cycle Stages / drug effects
  • Malaria / drug therapy
  • Malaria / immunology
  • Malaria / parasitology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Molecular Weight
  • Movement / drug effects
  • Oligonucleotide Array Sequence Analysis / methods
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / enzymology*
  • Plasmodium falciparum / growth & development
  • Protein Kinases / drug effects*
  • Protein Kinases / genetics*
  • Protein Kinases / physiology
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / physiology
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Small Molecule Libraries
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • Antimalarials
  • Cyclohexylamines
  • Protozoan Proteins
  • Recombinant Proteins
  • Small Molecule Libraries
  • purfalcamine
  • Protein Kinases
  • calcium-dependent protein kinase-1, Plasmodium falciparum
  • Adenine

Associated data

  • PubChem-Substance/49681201
  • PubChem-Substance/49681202
  • PubChem-Substance/49681203
  • PubChem-Substance/49681204
  • PubChem-Substance/49681205
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