ArticleAntimicrobial agents and chemotherapy2011
Selective inhibitors of methionyl-tRNA synthetase have potent activity against Trypanosoma brucei Infection in Mice.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 77 citations in OpenAlex.
- Discovery of a triple-site inhibitor targeting bacterial methionyl-tRNA synthetase through combined drug repurposing screening and generative AI-assisted optimization.Nucleic acids research · 2026Article
- Transcriptome Analysis of Trigeminal Ganglion and Medullary Dorsal Horn in Mice to Identify Potential Targets for Pulpitis-Induced Pain.ACS omega · 2025Article
- Small Molecule Inhibitors against the Bacterial PathogenCurrent medicinal chemistry · 2024Review
- ExploringPharmaceuticals (Basel, Switzerland) · 2023Article
- Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites.ACS omega · 2023Review
- Microbial Genomics: Innovative Targets and Mechanisms.Antibiotics (Basel, Switzerland) · 2023Review
- Synthesis and Structure-Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases.ChemMedChem · 2021Article
- Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery.International journal of molecular sciences · 2021Review
- Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity againstRSC medicinal chemistry · 2020Article
- Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase.ACS infectious diseases · 2020Article
- Design, Synthesis, and Evaluation of Novel Anti-Trypanosomal Compounds.Tetrahedron · 2020Article
- A suite of phenotypic assays to ensure pipeline diversity when prioritizing drug-like Cryptosporidium growth inhibitors.Nature communications · 2019Article
- Optimization of Methionyl tRNA-Synthetase Inhibitors for Treatment ofAntimicrobial agents and chemotherapy · 2019Article
- Aminoacyl tRNA synthetases as malarial drug targets: a comparative bioinformatics study.Malaria journal · 2019Article
- Review
- The crystal structure of the drug target Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with a catalytic intermediate.Acta crystallographica. Section F, Structural biology communications · 2018Article
- Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections.Antimicrobial agents and chemotherapy · 2017Article
- Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani.ACS infectious diseases · 2017Article
- Novel lead compounds in pre-clinical development against African sleeping sickness.MedChemComm · 2017Review
- Article
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
Abstract
Human African trypanosomiasis continues to be an important public health threat in extensive regions of sub-Saharan Africa. Treatment options for infected patients are unsatisfactory due to toxicity, difficult administration regimes, and poor efficacy of available drugs. The aminoacyl-tRNA synthetases were selected as attractive drug targets due to their essential roles in protein synthesis and cell survival. Comparative sequence analysis disclosed differences between the trypanosome and mammalian methionyl-tRNA synthetases (MetRSs) that suggested opportunities for selective inhibition using drug-like molecules. Experiments using RNA interference on the single MetRS of Trypanosoma brucei demonstrated that this gene product was essential for normal cell growth. Small molecules (diaryl diamines) similar to those shown to have potent activity on prokaryotic MetRS enzymes were synthesized and observed to have inhibitory activity on the T. brucei MetRS (50% inhibitory concentration, <50 nM) and on bloodstream forms of T. brucei cultures (50% effective concentration, as low as 4 nM). Twenty-one compounds had a close correlation between enzyme binding/inhibition and T. brucei growth inhibition, indicating that they were likely to be acting on the intended target. The compounds had minimal effects on mammalian cell growth at 20 μM, demonstrating a wide therapeutic index. The most potent compound was tested in the murine model of trypanosomiasis and demonstrated profound parasite suppression and delayed mortality. A homology model of the T. brucei MetRS based on other MetRS structures was used to model binding of the lead diaryl diamine compounds. Future studies will focus on improving the pharmacological properties of the MetRS inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.