Back to Search
Start Over
Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2008 Jun; Vol. 4 (6), pp. 347-56. Date of Electronic Publication: 2008 May 04. - Publication Year :
- 2008
-
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.
- Subjects :
- Adenine chemistry
Adenine pharmacology
Adenine therapeutic use
Animals
Antimalarials chemistry
Antimalarials therapeutic use
CHO Cells
Cell Line
Cell Proliferation drug effects
Cricetinae
Cricetulus
Cyclohexylamines chemistry
Cyclohexylamines therapeutic use
Drug Evaluation, Preclinical
Enzyme Activation drug effects
Gene Expression Regulation, Enzymologic drug effects
HeLa Cells
Humans
Life Cycle Stages drug effects
Malaria drug therapy
Malaria immunology
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 growth & development
Protein Kinases physiology
Protozoan Proteins genetics
Protozoan Proteins physiology
Recombinant Proteins antagonists & inhibitors
Recombinant Proteins genetics
Small Molecule Libraries
Stereoisomerism
Structure-Activity Relationship
Tissue Distribution
Adenine analogs & derivatives
Antimalarials pharmacology
Cyclohexylamines pharmacology
Gene Expression Regulation, Enzymologic genetics
Malaria parasitology
Plasmodium falciparum enzymology
Protein Kinases drug effects
Protein Kinases genetics
Protozoan Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 4
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 18454143
- Full Text :
- https://doi.org/10.1038/nchembio.87