Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo.
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| 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.
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| Authors | Eva Maria Novoa, Noelia Camacho, Anna Tor, Barrie Wilkinson, Steven Moss, Patricia Marín-García, Isabel G Azcárate, José M Bautista, Adam C Mirando, Christopher S Francklyn, Sònia Varon, Miriam Royo, Alfred Cortés, Lluís Ribas de Pouplana |
| Journal | Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 51 Pg. E5508-17 (Dec 23 2014) ISSN: 1091-6490 [Electronic] United States |
| PMID | 25489076 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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