title: Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo.
abstract: Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo.
authors.affiliation: Institute for Research in Biomedicine, 08028 Barcelona, Catalonia, Spain;
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Novoa
authors.affiliation: Institute for Research in Biomedicine, 08028 Barcelona, Catalonia, Spain;
authors.forename: Noelia
authors.initials: N
authors.lastname: Camacho
authors.affiliation: Institute for Research in Biomedicine, 08028 Barcelona, Catalonia, Spain;
authors.forename: Anna
authors.initials: A
authors.lastname: Tor
authors.affiliation: Biotica Technology Ltd., Cambridge CB21 6AD, United Kingdom; Isomerase Therapeutics Ltd., Cambridge CB10 1XL, United Kingdom;
authors.forename: Barrie
authors.initials: B
authors.lastname: Wilkinson
authors.affiliation: Biotica Technology Ltd., Cambridge CB21 6AD, United Kingdom; Isomerase Therapeutics Ltd., Cambridge CB10 1XL, United Kingdom;
authors.forename: Steven
authors.initials: S
authors.lastname: Moss
authors.affiliation: Department of Biochemistry and Molecular Biology IV and Research Institute Hospital 12 de Octubre, Complutense University of Madrid, 28040 Madrid, Spain; Health Sciences School, Medical Immunology Unit, Rey Juan Carlos University, 28922 Alcorcón (Madrid), Spain;
authors.forename: Patricia
authors.initials: P
authors.lastname: Marín-García
authors.affiliation: Department of Biochemistry and Molecular Biology IV and Research Institute Hospital 12 de Octubre, Complutense University of Madrid, 28040 Madrid, Spain;
authors.forename: Isabel G
authors.initials: IG
authors.lastname: Azcárate
authors.affiliation: Department of Biochemistry and Molecular Biology IV and Research Institute Hospital 12 de Octubre, Complutense University of Madrid, 28040 Madrid, Spain;
authors.forename: José M
authors.initials: JM
authors.lastname: Bautista
authors.affiliation: Department of Biochemistry and Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT 05405;
authors.forename: Adam C
authors.initials: AC
authors.lastname: Mirando
authors.affiliation: Department of Biochemistry and Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT 05405;
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Francklyn
authors.affiliation: Combinatorial Chemistry Unit, University of Barcelona, 08028 Barcelona, Catalonia, Spain;
authors.forename: Sònia
authors.initials: S
authors.lastname: Varon
authors.affiliation: Combinatorial Chemistry Unit, University of Barcelona, 08028 Barcelona, Catalonia, Spain; Bioengineering Biomaterial and Nanomedicine Networking Center, 08028 Barcelona, Catalonia, Spain; and.
authors.forename: Miriam
authors.initials: M
authors.lastname: Royo
authors.affiliation: Institute for Research in Biomedicine, 08028 Barcelona, Catalonia, Spain; Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Catalonia, Spain.
authors.forename: Alfred
authors.initials: A
authors.lastname: Cortés
authors.affiliation: Institute for Research in Biomedicine, 08028 Barcelona, Catalonia, Spain; Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Catalonia, Spain lluis.ribas@irbbarcelona.org.
authors.forename: Lluís
authors.initials: L
authors.lastname: Ribas de Pouplana
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D000604:Amino Acyl-tRNA Synthetases
keywords: aminoacyl-tRNA synthetase; borrelidin; drug design; malaria; plasmodium