ArticlePLoS pathogens2022
Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development.
Article in PLoS pathogens, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 26 citations in OpenAlex.
- An IL-1, IL-17, and IL-22 cytokine circuit controls vulvovaginal candidiasis independently of estrogen.PLoS pathogens · 2026Article
- N-(9-Acridinyl) Amino Acid Derivatives: Synthesis and In Vitro Evaluation of Anti-Pharmaceutics · 2025Article
- ATP mimetics targeting prolyl-tRNA synthetases as a new avenue for antimalarial drug development.iScience · 2024Article
- Adaptation of a eukaryote-like ProRS to a prokaryote-like tRNAPro.Nucleic acids research · 2024Article
- Adaptive evolution: Eukaryotic enzyme's specificity shift to a bacterial substrate.Protein science : a publication of the Protein Society · 2024Article
- Evodiamine inhibits EPRS expression to regulate glutamate metabolism and proliferation of oral squamous cell carcinoma cells.The Kaohsiung journal of medical sciences · 2024Article
- Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites.ACS omega · 2023Review
- Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondii.Scientific reports · 2023Article
- The binding mode of orphan glycyl-tRNA synthetase with tRNA supports the synthetase classification and reveals large domain movements.Science advances · 2023Article
- Targeting prolyl-tRNA synthetase via a series of ATP-mimetics to accelerate drug discovery against toxoplasmosis.PLoS pathogens · 2023Article
- New targets for antimalarial drug discovery.Current opinion in microbiology · 2022Review
- Genomic analysis of single nucleotide polymorphisms in malaria parasite drug targets.Parasites & vectors · 2022Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Toxoplasmosis is caused by Toxoplasma gondii and in immunocompromised patients it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) is a validated druggable target in Toxoplasma gondii but the traditional 'single target-single drug' approach has its caveats. Here, we describe two potent inhibitors namely halofuginone (HFG) and a novel ATP mimetic (L95) that bind to Toxoplasma gondii PRS simultaneously at different neighbouring sites to cover all three of the enzyme substrate subsites. HFG and L95 act as one triple-site inhibitor in tandem and form an unusual ternary complex wherein HFG occupies the 3'-end of tRNA and the L-proline (L-pro) binding sites while L95 occupies the ATP pocket. These inhibitors exhibit nanomolar IC50 and EC50 values independently, and when given together reveal an additive mode of action in parasite inhibition assays. This work validates a novel approach and lays a structural framework for further drug development based on simultaneous targeting of multiple pockets to inhibit druggable proteins.
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