Inhibition of invasion and intraerythrocytic development of Plasmodium falciparum by kinase inhibitors.
We have examined the effects of seven protein kinase inhibitors (staurosporine, genistein, methyl 2,5-dihydroxycinnamate, tyrphostins B44 and B46, lavendustin A and R03) on the erythrocytic cycle of the malaria parasite, Plasmodium falciparum. One (staurosporine) strongly inhibits serine/threonine kinases, but the remainder all exhibit a strong preference for tyrosine kinases. We have been able to discriminate between effects on invasion and on intraerythrocytic development. All reagents impeded development of intraerythrocytic parasites, though at widely differing concentrations, from the sub-micromolar to the millimolar. Several inhibitors, including staurosporine, also reduced invasion. The phosphatase inhibitor, okadaic acid, had a strong inhibitory effect both on invasion and development. The regulation of malaria development by phosphorylation or dephosphorylation reactions at several points in the blood-stage cycle is implied.
Dluzewski
A R
AR
Medical Research Council, Muscle and Cell Motility Unit, King's College, London, United Kingdom.
Garcia
C R
CR
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology*; D004988:Ethers, Cyclic / Q000494:pharmacology; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019319:Okadaic Acid; D010636:Phenols / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development*; D047428:Protein Kinase Inhibitors; D019311:Staurosporine; D020032:Tyrphostins
D000470:Alkaloids; D000962:Antimalarials; D001597:Benzylidene Compounds; D002934:Cinnamates; D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D007529:Isoflavones; D009570:Nitriles; D010636:Phenols; D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; C095713:alpha-cyano-(3,4-dihydroxy)-N-(3-phenylpropyl)cinnamide; C100661:tyrphostin B44; D019319:Okadaic Acid; C062898:lavendustin A; C067472:methyl 2,5-dihydroxycinnamate; D019833:Genistein; D010744:Phosphoric Monoester Hydrolases; D019311:Staurosporine