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Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2020 Nov 18; Vol. 48 (20), pp. 11566-11576. - Publication Year :
- 2020
-
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.<br /> (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Anaplastic Lymphoma Kinase antagonists & inhibitors
Animals
Antimalarials chemistry
Enzyme Inhibitors chemistry
Humans
Lysine-tRNA Ligase chemistry
Models, Molecular
Plasmodium falciparum drug effects
Protein Biosynthesis drug effects
Protein Conformation drug effects
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Rabbits
Structure-Activity Relationship
Sulfones chemistry
Sulfones pharmacology
Triazines chemistry
Triazines pharmacology
Antimalarials pharmacology
Enzyme Inhibitors pharmacology
Lysine-tRNA Ligase antagonists & inhibitors
Plasmodium falciparum enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 48
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 33053158
- Full Text :
- https://doi.org/10.1093/nar/gkaa862