4.8 Article

Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32630-4

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资金

  1. NIH [R01AI143723, R01AI152533, 5F31AI129412]
  2. Bill & Melinda Gates Foundation [OPP1054480]
  3. Leducq Foundation
  4. Arthritis Research UK [20522]
  5. Cancer Research UK [A23900]
  6. National Science Foundation Graduate Research Fellowship [DGE1745303]
  7. Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences [T32 GM008666]
  8. National Institutes of Health SIG grant [S10 OD026929]

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This article describes a biochemical assay for the development of antimalarials targeted at the prolyl-tRNA synthetase enzyme. High-affinity inhibitors, including triple-site ligands, were developed using this assay. These inhibitors exhibit potent dual-stage activity against Plasmodium parasites and show good cellular host selectivity. This research provides insights for the rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies.
The development of antimalarials against the human liver and asexual blood stages is one of the top public health challenges. Here, the authors report a single-step biochemical assay for the characterization of prolyl-tRNA synthetase inhibitors, and develop high-affinity inhibitors for the enzyme, including elusive triple-site ligands. The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world's most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility. Supported by this assay platform and co-crystal structures of representative inhibitor-target complexes, we develop a set of high-affinity prolyl-tRNA synthetase inhibitors, including previously elusive aminoacyl-tRNA synthetase triple-site ligands that simultaneously engage all three substrate-binding pockets. Several compounds exhibit potent dual-stage activity against Plasmodium parasites and display good cellular host selectivity. Our data inform the inhibitor requirements to overcome existing resistance mechanisms and establish a path for rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies.

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