ArticleAntimicrobial agents and chemotherapy2015
Inhibition of protein synthesis and malaria parasite development by drug targeting of methionyl-tRNA synthetases.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 51 citations in OpenAlex.
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- Genetic crosses within and between species ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Discovery of two distinct aminoacyl-tRNA synthetase complexes anchored to the Plasmodium surface tRNA import protein.The Journal of biological chemistry · 2022Article
- Sparsomycin Exhibits Potent Antiplasmodial Activity In Vitro and In Vivo.Pharmaceutics · 2022Article
- Discovery of novel antituberculosis agents among 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives targeting aminoacyl-tRNA synthetases.Scientific reports · 2021Article
- Design and tests of prospective property predictions for novel antimalarial 2-aminopropylaminoquinolones.Journal of computer-aided molecular design · 2020Article
- Bicyclic azetidines kill the diarrheal pathogenScience translational medicine · 2020Article
- Novel chloroquine loaded curcumin based anionic linear globular dendrimer G2: a metabolomics study onParasitology · 2020Article
- Identification of Selective Novel Hits againstInternational journal of molecular sciences · 2020Article
- Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase.ACS infectious diseases · 2020Article
- Analysis of the active fraction of IranianIranian journal of basic medical sciences · 2020Article
- Low-Complexity Repetitive Epitopes ofFrontiers in immunology · 2020Article
- Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases amongMedChemComm · 2019Article
- Conformational heterogeneity in apo and drug-bound structures of Toxoplasma gondii prolyl-tRNA synthetase.Acta crystallographica. Section F, Structural biology communications · 2019Article
- Dual-targeted hit identification using pharmacophore screening.Journal of computer-aided molecular design · 2019Article
- Aminoacyl tRNA synthetases as potential drug targets of the Panthera pathogen Babesia.Parasites & vectors · 2019Article
- Article
- Aminoacyl tRNA synthetases as malarial drug targets: a comparative bioinformatics study.Malaria journal · 2019Article
- The Plasmodium falciparum cytoplasmic translation apparatus: a promising therapeutic target not yet exploited by clinically approved anti-malarials.Malaria journal · 2018Article
- Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS(cyt) and PfMRS(api). Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS(cyt)) or proteobacteria/primitive bacteria (PfMRS(api)). We show that PfMRS(cyt) localizes in parasite cytoplasm, while PfMRS(api) localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with (35)S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs.
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