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

Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5508-17. doi: 10.1073/pnas.1405994111. Epub 2014 Dec 8.


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.

Keywords: aminoacyl-tRNA synthetase; borrelidin; drug design; malaria; plasmodium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acyl-tRNA Synthetases / antagonists & inhibitors*
  • Animals
  • Antimalarials / pharmacology
  • Antimalarials / therapeutic use*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Malaria, Falciparum / drug therapy*
  • Mice
  • Plasmodium falciparum / drug effects


  • Antimalarials
  • Enzyme Inhibitors
  • Amino Acyl-tRNA Synthetases