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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 <jats:italic>Plasmodium<\/jats:italic> 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 <jats:italic>Plasmodium<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41467-022-32630-4","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T09:03:59Z","timestamp":1661418239000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone\u00a0resistance"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9456-0767","authenticated-orcid":false,"given":"Mark A.","family":"Tye","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9513-6194","authenticated-orcid":false,"given":"N. 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