title: Chemical interrogation of the malaria kinome.
abstract: Malaria, an infectious disease caused by eukaryotic parasites of the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analyses of parasite genomes predict at least 65 protein kinases, but their biological functions and therapeutic potential are largely unknown. We profiled 1358 small-molecule kinase inhibitors to evaluate the role of both the human and the malaria kinomes in Plasmodium infection of liver cells, the parasites' obligatory but transient developmental stage that precedes the symptomatic blood stage. The screen identified several small molecules that inhibit parasite load in liver cells, some with nanomolar efficacy, and each compound was subsequently assessed for activity against blood-stage malaria. Most of the screening hits inhibited both liver- and blood-stage malaria parasites, which have dissimilar gene expression profiles and infect different host cells. Evaluation of existing kinase activity profiling data for the library members suggests that several kinases are essential to malaria parasites, including cyclin-dependent kinases (CDKs), glycogen synthase kinases, and phosphoinositide-3-kinases. CDK inhibitors were found to bind to Plasmodium protein kinase 5, but it is likely that these compounds target multiple parasite kinases. The dual-stage inhibition of the identified kinase inhibitors makes them useful chemical probes and promising starting points for antimalarial development.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 (USA). emily.derbyshire@duke.edu.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Derbyshire
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zuzarte-Luís
authors.forename: Andreia D
authors.initials: AD
authors.lastname: Magalhães
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kato
authors.forename: Paul C
authors.initials: PC
authors.lastname: Sanschagrin
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Chandrasekhar V
authors.initials: CV
authors.lastname: Miduturu
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Piotr
authors.initials: P
authors.lastname: Sliz
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D018503:Genome, Protozoan / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000235:genetics* / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010961:Plasmodium / Q000201:enzymology / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics*; D054852:Small Molecule Libraries
chemical_list: D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011494:Protein Kinases
keywords: Plasmodium; bioinformatics; chemical probes; high-throughput screening; kinases; malaria
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