title: Targeting Plasmodium falciparum protein kinases with adenosine analogue-oligoarginine conjugates.
abstract: During the last decade, a vast number of inhibitors, ligands and fluorescent probes have evolved for mammalian protein kinases; however, the suitability of these compounds for studies of evolutionarily divergent eukaryotes has mostly been left beyond the scope of research. Here, we examined whether adenosine analogue-oligoarginine conjugates that had been extensively characterized as efficient inhibitors of the human protein kinases are applicable for targeting Plasmodium protein kinases. We demonstrated that ARCs were not only able to bind to and inhibit a representative member of Plasmodium falciparum kinome (cGMP-dependent protein kinase) in biochemical assay, but also affected the general phosphorylation levels in parasites released from the infected red blood cells upon saponin treatment. These findings urge advantaging of already existing biochemical tools, whose initially generic, but intrinsically "tunable" selectivity profiles could be used for dissection of signaling pathways outside the initially defined group of biological targets.
authors.affiliation: Institute of Chemistry, University of Tartu, Estonia.
authors.forename: Darja
authors.initials: D
authors.lastname: Lavogina
authors.affiliation: Department of Physiology, Institute of Biosciences, University of Sao Paulo, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Budu
authors.affiliation: Institute of Chemistry, University of Tartu, Estonia.
authors.forename: Erki
authors.initials: E
authors.lastname: Enkvist
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Hopp
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes Cité Sorbonne, Paris, France.
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
authors.affiliation: Department of Physiology, Institute of Biosciences, University of Sao Paulo, Brazil. Electronic address: cgarcia@usp.br.
authors.forename: Celia R S
authors.initials: CR
authors.lastname: Garcia
authors.affiliation: Institute of Chemistry, University of Tartu, Estonia. Electronic address: asko.uri@ut.ee.
authors.forename: Asko
authors.initials: A
authors.lastname: Uri
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives*; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005456:Fluorescent Dyes / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007091:Image Processing, Computer-Assisted; D016778:Malaria, Falciparum / Q000188:drug therapy; D018613:Microscopy, Confocal; D018512:Parasitemia / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D005456:Fluorescent Dyes; D047428:Protein Kinase Inhibitors; D017869:Cyclic GMP-Dependent Protein Kinases; D000241:Adenosine
keywords: ARC; Fluorescence anisotropy; Malaria; PfPKG; Protein kinase