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Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5508-17. doi: 10.1073/pnas.1405994111. Epub 2014 Dec 8.

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

Author information

1
Institute for Research in Biomedicine, 08028 Barcelona, Catalonia, Spain;
2
Biotica Technology Ltd., Cambridge CB21 6AD, United Kingdom; Isomerase Therapeutics Ltd., Cambridge CB10 1XL, United Kingdom;
3
Department of Biochemistry and Molecular Biology IV and Research Institute Hospital 12 de Octubre, Complutense University of Madrid, 28040 Madrid, Spain; Health Sciences School, Medical Immunology Unit, Rey Juan Carlos University, 28922 Alcorcón (Madrid), Spain;
4
Department of Biochemistry and Molecular Biology IV and Research Institute Hospital 12 de Octubre, Complutense University of Madrid, 28040 Madrid, Spain;
5
Department of Biochemistry and Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT 05405;
6
Combinatorial Chemistry Unit, University of Barcelona, 08028 Barcelona, Catalonia, Spain;
7
Combinatorial Chemistry Unit, University of Barcelona, 08028 Barcelona, Catalonia, Spain; Bioengineering Biomaterial and Nanomedicine Networking Center, 08028 Barcelona, Catalonia, Spain; and.
8
Institute for Research in Biomedicine, 08028 Barcelona, Catalonia, Spain; Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Catalonia, Spain.
9
Institute for Research in Biomedicine, 08028 Barcelona, Catalonia, Spain; Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Catalonia, Spain lluis.ribas@irbbarcelona.org.

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.

KEYWORDS:

aminoacyl-tRNA synthetase; borrelidin; drug design; malaria; plasmodium

PMID:
25489076
PMCID:
PMC4280603
DOI:
10.1073/pnas.1405994111
[Indexed for MEDLINE]
Free PMC Article

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