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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemistry
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Adenine / pharmacology
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Adenine / therapeutic use
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Animals
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Antimalarials / chemistry
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Antimalarials / pharmacology*
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Antimalarials / therapeutic use
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CHO Cells
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Cell Line
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Cell Proliferation / drug effects
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Cricetinae
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Cricetulus
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Cyclohexylamines / chemistry
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Cyclohexylamines / pharmacology*
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Cyclohexylamines / therapeutic use
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Drug Evaluation, Preclinical
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Enzyme Activation / drug effects
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics*
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HeLa Cells
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Humans
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Life Cycle Stages / drug effects
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Malaria / drug therapy
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Malaria / immunology
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Malaria / parasitology*
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Male
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Mice
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Mice, Inbred BALB C
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Models, Molecular
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Molecular Structure
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Molecular Weight
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Movement / drug effects
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Oligonucleotide Array Sequence Analysis / methods
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Parasitic Sensitivity Tests
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Plasmodium falciparum / enzymology*
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Plasmodium falciparum / growth & development
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Protein Kinases / drug effects*
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Protein Kinases / genetics*
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Protein Kinases / physiology
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / genetics
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Protozoan Proteins / physiology
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / genetics
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Small Molecule Libraries
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Stereoisomerism
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Structure-Activity Relationship
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Tissue Distribution
Substances
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Antimalarials
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Cyclohexylamines
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Protozoan Proteins
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Recombinant Proteins
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Small Molecule Libraries
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purfalcamine
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Protein Kinases
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calcium-dependent protein kinase-1, Plasmodium falciparum
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Adenine
Associated data
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PubChem-Substance/49681201
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PubChem-Substance/49681202
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PubChem-Substance/49681203
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PubChem-Substance/49681204
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PubChem-Substance/49681205
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PubChem-Substance/49681206
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PubChem-Substance/49681207
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PubChem-Substance/49681208
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PubChem-Substance/49681209
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PubChem-Substance/49681210
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PubChem-Substance/49681211
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PubChem-Substance/49681212
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PubChem-Substance/49681213
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PubChem-Substance/49681214
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PubChem-Substance/49681216
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PubChem-Substance/49681219
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PubChem-Substance/49681220
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PubChem-Substance/49681221
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PubChem-Substance/49681222
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PubChem-Substance/49681234
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PubChem-Substance/49681238
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PubChem-Substance/49681239
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PubChem-Substance/49681240
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PubChem-Substance/49681247
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PubChem-Substance/49681248
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PubChem-Substance/49681255
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PubChem-Substance/49681256
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PubChem-Substance/49681257
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PubChem-Substance/49681258
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PubChem-Substance/49681259
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PubChem-Substance/49681260