Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo
Significance Malaria remains one of the main health threats in the developing world, with staggering social and economic costs. Resistance to artemisins, the main pharmacological tool currently available against malaria, has been widely reported. Borrelidin, a natural compound that inhibits threonyl...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 51; pp. E5508 - E5517 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
23.12.2014
National Acad Sciences |
Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
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Abstract | Significance Malaria remains one of the main health threats in the developing world, with staggering social and economic costs. Resistance to artemisins, the main pharmacological tool currently available against malaria, has been widely reported. Borrelidin, a natural compound that inhibits threonyl-tRNA synthetase, has long been studied for its antibacterial and antiparasitic properties, but undesirable toxic effects prevented its further clinical development. Here we present a group of borrelidin derivatives that retain their ability to inhibit Plasmodium threonyl-tRNA synthetase but not its human homolog. Furthermore, we demonstrate, for the first time to our knowledge, that these compounds are capable of effectively clearing a Plasmodium infection in animals, curing malaria with a potency equivalent to reference drugs such as chloroquine.
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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AbstractList | 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. Malaria remains one of the main health threats in the developing world, with staggering social and economic costs. Resistance to artemisins, the main pharmacological tool currently available against malaria, has been widely reported. Borrelidin, a natural compound that inhibits threonyl-tRNA synthetase, has long been studied for its antibacterial and antiparasitic properties, but undesirable toxic effects prevented its further clinical development. Here we present a group of borrelidin derivatives that retain their ability to inhibit Plasmodium threonyl-tRNA synthetase but not its human homolog. Furthermore, we demonstrate, for the first time to our knowledge, that these compounds are capable of effectively clearing a Plasmodium infection in animals, curing malaria with a potency equivalent to reference drugs such as chloroquine. 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. Significance Malaria remains one of the main health threats in the developing world, with staggering social and economic costs. Resistance to artemisins, the main pharmacological tool currently available against malaria, has been widely reported. Borrelidin, a natural compound that inhibits threonyl-tRNA synthetase, has long been studied for its antibacterial and antiparasitic properties, but undesirable toxic effects prevented its further clinical development. Here we present a group of borrelidin derivatives that retain their ability to inhibit Plasmodium threonyl-tRNA synthetase but not its human homolog. Furthermore, we demonstrate, for the first time to our knowledge, that these compounds are capable of effectively clearing a Plasmodium infection in animals, curing malaria with a potency equivalent to reference drugs such as chloroquine. 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. |
Author | Isabel G. Azcárate Anna Tor Noelia Camacho Barrie Wilkinson Adam C. Mirando Steven Moss Eva Maria Novoa Alfred Cortés Miriam Royo Patricia Marín-García Lluís Ribas de Pouplana Sònia Varon José M. Bautista Christopher S. Francklyn |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25489076$$D View this record in MEDLINE/PubMed |
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Notes | http://dx.doi.org/10.1073/pnas.1405994111 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Susan A. Martinis, University of Illinois, Urbana, IL, and accepted by the Editorial Board November 10, 2014 (received for review April 4, 2014) 3Present address: Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), 08036 Barcelona, Spain. 1Present address: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139. 2Present address: John Innes Centre, Norwich NR4 7UH, United Kingdom. Author contributions: E.M.N., M.R., A.C., and L.R.d.P. designed research; E.M.N., N.C., A.T., P.M.-G., I.G.A., J.M.B., A.C.M., C.S.F., and S.V. performed research; B.W., S.M., and A.C. contributed new reagents/analytic tools; E.M.N., N.C., and L.R.d.P. analyzed data; and E.M.N. and L.R.d.P. wrote the paper. |
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Snippet | Significance Malaria remains one of the main health threats in the developing world, with staggering social and economic costs. Resistance to artemisins, the... Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein... Malaria remains one of the main health threats in the developing world, with staggering social and economic costs. Resistance to artemisins, the main... |
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SubjectTerms | Amino Acyl-tRNA Synthetases - antagonists & inhibitors Animals Antimalarials - pharmacology Antimalarials - therapeutic use Bioengineering Biological Sciences Biosynthesis Cytotoxicity Drug resistance Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Humans Malaria Malaria, Falciparum - drug therapy Mice Parasitic protozoa Plasmodium falciparum Plasmodium falciparum - drug effects PNAS Plus RNA-protein interactions |
Title | Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo |
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