Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility.
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.
Kato
Nobutaka
N
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND202 La Jolla, California 92037, USA.
Sakata
Tomoyo
T
Breton
Ghislain
G
Le Roch
Karine G
KG
Nagle
Advait
A
Andersen
Carsten
C
Bursulaya
Badry
B
Henson
Kerstin
K
Johnson
Jeffrey
J
Kumar
Kota Arun
KA
Marr
Felix
F
Mason
Daniel
D
McNamara
Case
C
Plouffe
David
D
Ramachandran
Vandana
V
Spooner
Muriel
M
Tuntland
Tove
T
Zhou
Yingyao
Y
Peters
Eric C
EC
Chatterjee
Arnab
A
Schultz
Peter G
PG
Ward
Gary E
GE
Gray
Nathanael
N
Harper
Jeffrey
J
Winzeler
Elizabeth A
EA
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003514:Cyclohexylamines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009068:Movement / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000254:growth & development; D011494:Protein Kinases / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D000962:Antimalarials; D003514:Cyclohexylamines; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; C531239:purfalcamine; D011494:Protein Kinases; C531238:calcium-dependent protein kinase-1, Plasmodium falciparum; D000225:Adenine