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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.

SUBMITTER: Novoa EM 

PROVIDER: S-EPMC4280603 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Novoa Eva Maria EM   Camacho Noelia N   Tor Anna A   Wilkinson Barrie B   Moss Steven S   Marín-García Patricia P   Azcárate Isabel G IG   Bautista José M JM   Mirando Adam C AC   Francklyn Christopher S CS   Varon Sònia S   Royo Miriam M   Cortés Alfred A   Ribas de Pouplana Lluís L  

Proceedings of the National Academy of Sciences of the United States of America 20141208 51


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-tRN  ...[more]

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