Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo. [artículo]
Por: Azcárate, Isabel G [Instituto de Investigación imas12] | Bautista, José M [Instituto de Investigación i+12].
Colaborador(es): Instituto de Investigación imas12.
Tipo de material: ArtículoEditor: Proceedings of the National Academy of Sciences of the United States of America, 2014Descripción: 111(51):E5508-17.Recursos en línea: Acceso libre Resumen: 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.Tipo de ítem | Ubicación actual | Signatura | Estado | Fecha de vencimiento |
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Artículo | Disponible |
Navegando Hospital Universitario 12 de Octubre Estantes Cerrar el navegador de estanterías
Formato Vancouver:
Novoa EM, Camacho N, Tor A, Wilkinson B, Moss S, Marín-García P et al. 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.
PMID: 25489076
PMC4280603
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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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