title: Selective inhibition of an apicoplastic aminoacyl-tRNA synthetase from Plasmodium falciparum.
abstract: The resistance of malaria parasites to available drugs continues to grow, and this makes the need for new antimalarial therapies pressing. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes and well-established antibacterial targets and so constitute a promising set of targets for the development of new antimalarials. Despite their potential as drug targets, apicoplastic ARSs remain unexplored. We have characterized the lysylation system of Plasmodium falciparum, and designed, synthesized, and tested a set of inhibitors based on the structure of the natural substrate intermediate: lysyl-adenylate. Here we demonstrate that selective inhibition of apicoplastic ARSs is feasible and describe new compounds that that specifically inhibit Plasmodium apicoplastic lysyl-tRNA synthetase and show antimalarial activities in the micromolar range.
authors: Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona, C/Baldiri Reixac 10, 08028 Barcelona, Catalonia, Spain.
authors: Rob
authors: R
authors: Hoen
authors: Eva Maria
authors: EM
authors: Novoa
authors: Alba
authors: A
authors: López
authors: Noelia
authors: N
authors: Camacho
authors: Laia
authors: L
authors: Cubells
authors: Pedro
authors: P
authors: Vieira
authors: Manuel
authors: M
authors: Santos
authors: Patricia
authors: P
authors: Marin-Garcia
authors: Jose Maria
authors: JM
authors: Bautista
authors: Alfred
authors: A
authors: Cortés
authors: Lluís
authors: L
authors: Ribas de Pouplana
authors: Miriam
authors: M
authors: Royo
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D000962:Antimalarials; C113976:lysyladenylate; D000249:Adenosine Monophosphate; D000604:Amino Acyl-tRNA Synthetases