title: Discovery and biochemical characterization of Plasmodium thioredoxin reductase inhibitors from an antimalarial set.
abstract: Plasmodium falciparum is the most prevalent and deadly species of the human malaria parasites, and thioredoxin reductase (TrxR) is an enzyme involved in the redox response to oxidative stress. Essential for P. falciparum survival, the enzyme has been highlighted as a promising target for novel antimalarial drugs. Here we report the discovery and characterization of seven molecules from an antimalarial set of 13533 compounds through single-target TrxR biochemical screens. We have produced high-purity, full-length, recombinant native enzyme from four Plasmodium species, and thioredoxin substrates from P. falciparum and Rattus norvegicus. The enzymes were screened using a unique, high-throughput, in vitro native substrate assay, and we have observed selectivity between the Plasmodium species and the mammalian form of the enzyme. This has indicated differences in their biomolecular profiles and has provided valuable insights into the biochemical mechanisms of action of compounds with proven antimalarial activity.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK. andrew.j.theobald@gsk.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Theobald
authors.forename: Iván
authors.initials: I
authors.lastname: Caballero
authors.forename: Isabel
authors.initials: I
authors.lastname: Coma
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Colmenarejo
authors.forename: Concepcion
authors.initials: C
authors.lastname: Cid
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hibbs
authors.forename: Amy L
authors.initials: AL
authors.lastname: Bass
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D015394:Molecular Structure; D010961:Plasmodium / Q000145:classification / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D013880:Thioredoxin-Disulfide Reductase