Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites

Pham, James S.; Dawson, Karen; Jackson, Katherine M.; Lim, Eun‐Pa; Pasaje, Charisse Flerida A.; Turner, Kelsey E.C.; Ralph, Stuart A.

doi:10.1016/j.ijpddr.2013.10.001

Cited by 117 publications

(113 citation statements)

References 115 publications

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“…There is increasing interest in the exploration of aminoacyltRNA synthetases as antimicrobial targets in both prokaryotic and eukaryotic pathogens (11,12). These enzymes catalyze the attachment (charging) of amino acids to their cognate tRNAs.…”

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confidence: 99%

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

Sonoiki

Palencia

Guo

et al. 2016

Antimicrob Agents Chemother

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There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum. Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC 50 ] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED 90 ], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [ 14 C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.

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confidence: 99%

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

Sonoiki

Palencia

Guo

et al. 2016

Antimicrob Agents Chemother

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“…AminoacyltRNA synthetases (aaRS) are required enzymes for protein translation and have been shown to be essential in genetic knockout or knockdown studies of various organisms, including yeast and protozoa (5-7). Inhibitors of aaRS enzymes have potent antibiotic, antifungal, and antiprotozoal activities with candidate compounds in preclinical and clinical development (7)(8)(9)(10)(11). Previous research by this group has led to the discovery of potent inhibitors of methionyl-tRNA synthetases (MetRS) of trypanosomatid parasites (8,12,13) and has demonstrated activity in animal models of Trypanosoma brucei infection (8,12).…”

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Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Giardia intestinalis Trophozoites

Ranade

Zhang

Gillespie

et al. 2015

Antimicrob Agents Chemother

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The methionyl-tRNA synthetase (MetRS) is a novel drug target for the protozoan pathogen Giardia intestinalis. This protist contains a single MetRS that is distinct from the human cytoplasmic MetRS. A panel of MetRS inhibitors was tested against recombinant Giardia MetRS, Giardia trophozoites, and mammalian cell lines. The best compounds inhibited trophozoite growth at 500 nM (metronidazole did so at ϳ5,000 nM) and had low cytotoxicity against mammalian cells, indicating excellent potential for further development as anti-Giardia drugs.

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“…While these enzymes are ubiquitous and essential for cellular life, they exhibit structural differences between phyla that can be exploited to develop drugs targeting pathogenic species, but that don't interact with the human counterpart [3]. During the past decade, natural and synthetic inhibitors targeting aaRSs from various human parasites and bacterial pathogens have been identified [3-5]. Most of these compounds bind to the synthetic sites of aaRSs and act as competitive inhibitors of the substrates for aminoacylation.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, inhibitors targeting the editing sites of aaRSs have also been discovered. Of the numerous inhibitors identified to date (for review see [3,5,6]), only two compounds are currently available for clinical use. These two inhibitors exhibit different modes of action with one targeting the aaRS synthetic site and the other targeting the editing site.…”

Section: Introductionmentioning

confidence: 99%

A continuous assay for monitoring the synthetic and proofreading activities of multiple aminoacyl-tRNA synthetases for high-throughput drug discovery

Grube

Roy

2017

RNA Biology

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Aminoacyl-tRNA synthetases (aaRSs) catalyze the aminoacylation of tRNAs to produce the aminoacyl-tRNAs (aa-tRNAs) required by ribosomes for translation of the genetic message into proteins. To ensure the accuracy of tRNA aminoacylation, and consequently the fidelity of protein synthesis, some aaRSs exhibit a proofreading (editing) site, distinct from the aa-tRNA synthetic site. The aaRS editing site hydrolyzes misacylated products formed when a non-cognate amino acid is used during tRNA charging. Because aaRSs play a central role in protein biosynthesis and cellular life, these proteins represent longstanding targets for therapeutic drug development to combat infectious diseases. Most existing aaRS inhibitors target the synthetic site, and it is only recently that drugs targeting the proofreading site have been considered. In the present study, we developed a robust assay for the high-throughput screening of libraries of inhibitors targeting both the synthetic and the proofreading sites of up to four aaRSs simultaneously. Thus, this assay allows for screening of eight distinct enzyme active sites in a single experiment. aaRSs from several prominent human pathogens (i.e., Mycobacterium tuberculosis, Plasmodium falciparum, and Escherichia coli) were used for development of this assay.

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Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites

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Cited by 117 publications

References 115 publications

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Giardia intestinalis Trophozoites

A continuous assay for monitoring the synthetic and proofreading activities of multiple aminoacyl-tRNA synthetases for high-throughput drug discovery

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