Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 51; pp. E5508 - E5517
• Main Authors: Novoa, Eva Maria, Camacho, Noelia, Tor, Anna, Wilkinson, Barrie, Moss, Steven, Marín-García, Patricia, Azcárate, Isabel G., Bautista, José M., Mirando, Adam C., Francklyn, Christopher S., Varon, Sònia, Royo, Miriam, Cortés, Alfred, Ribas de Pouplana, Lluís
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.12.2014; National Acad Sciences
• Series: PNAS Plus
• Subjects: Amino Acyl-tRNA Synthetases - antagonists & inhibitors; Animals; Antimalarials - pharmacology; Antimalarials - therapeutic use; Bioengineering; Biological Sciences; Biosynthesis; Cytotoxicity; Drug resistance; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Humans; Malaria; Malaria, Falciparum - drug therapy; Mice; Parasitic protozoa; Plasmodium falciparum; Plasmodium falciparum - drug effects; PNAS Plus; RNA-protein interactions; malaria; drug design; aminoacyl-tRNA synthetase; borrelidin; plasmodium
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1405994111

Significance Malaria remains one of the main health threats in the developing world, with staggering social and economic costs. Resistance to artemisins, the main pharmacological tool currently available against malaria, has been widely reported. Borrelidin, a natural compound that inhibits threonyl-tRNA synthetase, has long been studied for its antibacterial and antiparasitic properties, but undesirable toxic effects prevented its further clinical development. Here we present a group of borrelidin derivatives that retain their ability to inhibit Plasmodium threonyl-tRNA synthetase but not its human homolog. Furthermore, we demonstrate, for the first time to our knowledge, that these compounds are capable of effectively clearing a Plasmodium infection in animals, curing malaria with a potency equivalent to reference drugs such as chloroquine. 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.