ArticleNature communications2021
Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- Structure-Guided Optimization of Novel Inhibitors ofJournal of medicinal chemistry · 2026Article
- Indel-driven evolution of the canavanine tRNA-editing deacetylase enzyme CtdA.Journal of structural biology: X · 2025Article
- Improved Bicyclic Pyrrolidine Analogues InhibitJournal of medicinal chemistry · 2025Article
- Different chemical scaffolds bind to L-phe site in Mycobacterium tuberculosis Phe-tRNA synthetase.European journal of medicinal chemistry · 2025Article
- Antimalarial Drug Discovery from Natural and Synthetic Sources.Current medicinal chemistry · 2025Review
- Article
- ATP mimetics targeting prolyl-tRNA synthetases as a new avenue for antimalarial drug development.iScience · 2024Article
- Specific glycine-dependent enzyme motion determines the potency of conformation selective inhibitors of threonyl-tRNA synthetase.Communications biology · 2024Article
- Bicyclic Pyrrolidine Inhibitors ofACS infectious diseases · 2024Article
- Bicyclic pyrrolidine inhibitors ofbioRxiv : the preprint server for biology · 2024Article
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
- Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline.Microbiology spectrum · 2023Article
- Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites.ACS omega · 2023Review
- 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
- Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development.PLoS pathogens · 2022Article
- Bicyclic azetidines target acute and chronic stages of Toxoplasma gondii by inhibiting parasite phenylalanyl t-RNA synthetase.Nature communications · 2022Article
- Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue.Parasites & vectors · 2021Article
- Structural analyses of the malaria parasite aminoacyl-tRNA synthetases provide new avenues for antimalarial drug discovery.Protein science : a publication of the Protein Society · 2021Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
The inhibition of Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) by a novel series of bicyclic azetidines has shown the potential to prevent malaria transmission, provide prophylaxis, and offer single-dose cure in animal models of malaria. To date, however, the molecular basis of Plasmodium cFRS inhibition by bicyclic azetidines has remained unknown. Here, we present structural and biochemical evidence that bicyclic azetidines are competitive inhibitors of L-Phe, one of three substrates required for the cFRS-catalyzed aminoacylation reaction that underpins protein synthesis in the parasite. Critically, our co-crystal structure of a PvcFRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct sub-sites within the PvcFRS catalytic site. The ligand occupies the L-Phe site along with an auxiliary cavity and traverses past the ATP binding site. Given that BRD1389 recognition residues are conserved amongst apicomplexan FRSs, this work lays a structural framework for the development of drugs against both Plasmodium and related apicomplexans.
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