title: Characterization of Plasmodium liver stage inhibition by halofuginone.
abstract: Malaria is a devastating parasitic disease that afflicts one-third of the world's population. Antimalarial drugs in common use address few targets, and their efficacy is being undermined by parasite resistance. Most therapeutics target blood-stage malaria, whereas only few compounds are active against malaria's liver stage, the first stage of the Plasmodium parasite's life cycle within the human host. The identification of inhibitors active against liver-stage malaria would benefit the development of chemical probes to elucidate the poorly understood biology of this phase of the parasite life cycle and could provide agents to prevent and eliminate the disease. Herein we report the development of a live-cell parasite traversal assay in 384-well format amenable to high-throughput screening that exploits the wounding of liver cells by the parasite. This method identifies small molecules that may inhibit the parasite's actin-myosin motor system. The traversal assay, in addition to established methods, was used to evaluate the activity of halofuginone, a synthetic halogenated derivative of the natural alkaloid febrifugine, against liver-stage Plasmodium berghei parasites. Halofuginone was found to inhibit P. berghei sporozoite load in HepG2 cells with an IC(50) value of 17 nM. While the compound does not affect parasite traversal through human liver cells, an inhibition time course assay indicates that it affects essential processes in both early- and late-stage parasite development.
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Derbyshire
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D048749:Cytokinesis; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects* / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008954:Models, Biological; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D010962:Plasmodium berghei; D010963:Plasmodium falciparum; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D034101:Sporozoites / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D010880:Piperidines; D052999:Quinazolinones; C010176:halofuginone