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

EM Novoa, N Camacho, A Tor… - Proceedings of the …, 2014 - National Acad Sciences
EM Novoa, N Camacho, A Tor, B Wilkinson, S Moss, P Marin-Garcia, IG Azcárate
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
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 …
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.
National Acad Sciences
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