The growing pipeline of natural aminoacyl-tRNA synthetase inhibitors for malaria treatment

Saint-Léger, Adélaïde; Sinadinos, Christopher; Pouplana, Lluı́s Ribas de

doi:10.1080/21655979.2016.1149270

Cited by 23 publications

(24 citation statements)

References 37 publications

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“… 7 − 10 As a family, tRNA synthetases have also been shown to be good targets in the anti-infectives space. 11 − 13 MetRS was therefore prioritized as a target for entry into a Leishmania drug discovery program.…”

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confidence: 99%

Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani

et al. 2017

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Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study, we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki of 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately, this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable antileishmanial compound, MetRS remains an attractive antileishmanial drug target.

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confidence: 99%

Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani

et al. 2017

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“…A large number of natural products target various ARSs in Plasmodium falciparum (the causative agent of malaria), offering promise that this pathogen may well be the next eukaryotic target that yields a successful anti-ARS therapeutic (114,115). Malaria proceeds through multiple stages during its development, starting first with an insect form (the sporozoites), which upon transmission attacks liver cells (116).…”

Section: Malaria As a Target Of Anti-ars Compoundsmentioning

confidence: 99%

Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics

Francklyn

Mullen

2019

Journal of Biological Chemistry

113

104

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Edited by Karin Musier-Forsyth Aminoacyl-tRNA synthetases (ARSs) are universal enzymes that catalyze the attachment of amino acids to the 3 ends of their cognate tRNAs. The resulting aminoacylated tRNAs are escorted to the ribosome where they enter protein synthesis. By specifically matching amino acids to defined anticodon sequences in tRNAs, ARSs are essential to the physical interpretation of the genetic code. In addition to their canonical role in protein synthesis, ARSs are also involved in RNA splicing, transcriptional regulation, translation, and other aspects of cellular homeostasis. Likewise, aminoacylated tRNAs serve as amino acid donors for biosynthetic processes distinct from protein synthesis, including lipid modification and antibiotic biosynthesis. Thanks to the wealth of details on ARS structures and functions and the growing appreciation of their additional roles regulating cellular homeostasis, opportunities for the development of clinically useful ARS inhibitors are emerging to manage microbial and parasite infections. Exploitation of these opportunities has been stimulated by the discovery of new inhibitor frameworks, the use of semi-synthetic approaches combining chemistry and genome engineering, and more powerful techniques for identifying leads from the screening of large chemical libraries. Here, we review the inhibition of ARSs by small molecules, including the various families of natural products, as well as inhibitors developed by either rational design or highthroughput screening as antibiotics and anti-parasitic therapeutics.

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“…The compound thiaisoleucine, where γ-methylene of isoleucine was substituted by a sulfur atom, was found to potently inhibit cytosolic IRS, while another compound, mupirocin, a known inhibitor of methicillin-resistant S. aureus (MRSA) IRS, inhibited the apicoplast-localized IRS [22]. Of the 36 putative aminoacyl tRNA synthetases present in P. falciparum, nearly 5 have been targeted with potent inhibitors, and more are being tested [23,24].…”

Section: Hemoglobin Hydrolysismentioning

confidence: 99%

Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

Pasupureddy¹,

Seshadri²,

Dixit³

et al. 2020

Parasitology and Microbiology Research

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Malaria is one of the most deadly diseases infecting humans. Advances in elimination and vector control have reduced the global malaria burden in the past decade; however, the emerging threat of drug resistance and suboptimal vaccine efficacies threaten global eradication efforts. Unlocking novel drug and vaccine targets while simultaneously mitigating spread of resistant strains seems to be the need of the hour. Protein-protein interactions (PPIs), an integral part of hostpathogen cross-talk and parasite survival, have only recently emerged as promising drug targets. Large PPI networks (interactome) are being developed to better our understanding of various parasite biochemical pathways. In this chapter, we throw light on several newly characterized protein-protein interactions between the host (humans) and parasite (plasmodium) in key processes such as hemoglobin degradation, enzyme regulation, protein export, egress, invasion, and drug resistance and further discuss their viability for development as novel chemotherapeutic targets.

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The growing pipeline of natural aminoacyl-tRNA synthetase inhibitors for malaria treatment

Cited by 23 publications

References 37 publications

Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani

Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani

Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics

Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

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