Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase Journal Article
| Authors: | Xie, S. C.; Wang, Y.; Morton, C. J.; Metcalfe, R. D.; Dogovski, C.; Pasaje, C. F. A.; Dunn, E.; Luth, M. R.; Kumpornsin, K.; Istvan, E. S.; Park, J. S.; Fairhurst, K. J.; Ketprasit, N.; Yeo, T.; Yildirim, O.; Bhebhe, M. N.; Klug, D. M.; Rutledge, P. J.; Godoy, L. C.; Dey, S.; De Souza, M. L.; Siqueira-Neto, J. L.; Du, Y.; Puhalovich, T.; Amini, M.; Shami, G.; Loesbanluechai, D.; Nie, S.; Williamson, N.; Jana, G. P.; Maity, B. C.; Thomson, P.; Foley, T.; Tan, D. S.; Niles, J. C.; Han, B. W.; Goldberg, D. E.; Burrows, J.; Fidock, D. A.; Lee, M. C. S.; Winzeler, E. A.; Griffin, M. D. W.; Todd, M. H.; Tilley, L. |
| Article Title: | Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase |
| Abstract: | Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism. © 2024, The Author(s). |
| Keywords: | human cell; genetics; mutation; nonhuman; mass spectrometry; animal; metabolism; animals; protein; cytotoxicity; in vitro study; enzyme activity; inhibitor; structure activity relation; rna; sequence alignment; sulfonamide; mammal; amino acid; hydrogen bond; catalysis; toxicity; antimalarial agent; antimalarial activity; plasmodium falciparum; antimalarials; mammals; molecular weight; synthesis; asparagine; amino acid transfer rna ligase; rna, transfer, amino acyl; mammal cell; starvation; inhibition; cell; parasite; aminoacyl transfer rna; physical parameters; humans; human; article; kwashiorkor; nucleoside transporter; ic50; hep-g2 cell line; structural model; aspartate-trna ligase; asparaginyl-trna synthetase; aspartate transfer rna ligase; intrinsic clearance |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-01-31 |
| Start Page: | 937 |
| Language: | English |
| DOI: | 10.1038/s41467-024-45224-z |
| PUBMED: | 38297033 |
| PROVIDER: | scopus |
| PMCID: | PMC10831071 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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