ArticleNucleic acids research2020
Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor.
Article in Nucleic acids research, 2020. 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, 29 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
- Antimalarial Drug Discovery from Natural and Synthetic Sources.Current medicinal chemistry · 2025Review
- Specific glycine-dependent enzyme motion determines the potency of conformation selective inhibitors of threonyl-tRNA synthetase.Communications biology · 2024Article
- Structure-guided conversion from an anaplastic lymphoma kinase inhibitor into Plasmodium lysyl-tRNA synthetase selective inhibitors.Communications biology · 2024Article
- Competitive Inhibition of Okanin againstInternational journal of molecular sciences · 2024Article
- Human Polo-like Kinase Inhibitors as Antiplasmodials.ACS infectious diseases · 2023Article
- The binding mode of orphan glycyl-tRNA synthetase with tRNA supports the synthetase classification and reveals large domain movements.Science advances · 2023Article
- Synergetic delivery of artesunate and isosorbide 5-mononitrate with reduction-sensitive polymer nanoparticles for ovarian cancer chemotherapy.Journal of nanobiotechnology · 2022Article
- Genomic analysis of single nucleotide polymorphisms in malaria parasite drug targets.Parasites & vectors · 2022Article
- Functional characterization of 5' UTR cis-acting sequence elements that modulate translational efficiency in Plasmodium falciparum and humans.Malaria journal · 2022Article
- Biochemical characteristics of patients with imported malaria.Frontiers in cellular and infection microbiology · 2022Article
- Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery.International journal of molecular sciences · 2021Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aminoacyl-tRNA synthetases are attractive targets for the development of antibacterial, antifungal, antiparasitic agents and for the treatment of other human diseases. Lysyl-tRNA synthetase (LysRS) from this family has been validated as a promising target for the development of antimalarial drugs. Here, we developed a high-throughput compatible assay and screened 1215 bioactive compounds to identify Plasmodium falciparum cytoplasmic LysRS (PfLysRS) inhibitor. ASP3026, an anaplastic lymphoma kinase inhibitor that was used in clinical trials for the treatment of B-cell lymphoma and solid tumors, was identified as a novel PfLysRS inhibitor. ASP3026 suppresses the enzymatic activity of PfLysRS at nanomolar potency, which is >380-fold more effective than inhibition of the human counterpart. In addition, the compound suppressed blood-stage P. falciparum growth. To understand the molecular mechanism of inhibition by ASP3026, we further solved the cocrystal structure of PfLysRS-ASP3026 at a resolution of 2.49 Å, providing clues for further optimization of the compound. Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.
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