{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T07:13:50Z","timestamp":1778224430154,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010363","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T00:00:00Z","timestamp":1649721600000}}],"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"publisher","award":["P020\/00065"],"award-info":[{"award-number":["P020\/00065"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007225","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["PR32713"],"award-info":[{"award-number":["PR32713"]}],"id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["SB\/S2\/JCB-41\/2013"],"award-info":[{"award-number":["SB\/S2\/JCB-41\/2013"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001501","name":"University Grants Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001501","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Laboratoire d'Excellence","award":["ANR-11-LABX-0024"],"award-info":[{"award-number":["ANR-11-LABX-0024"]}]},{"name":"Agence Nationale pour la Recherche","award":["ANR-19-CE15-0026-01"],"award-info":[{"award-number":["ANR-19-CE15-0026-01"]}]},{"name":"Fondation pour la Recherche","award":["EQU202103012571"],"award-info":[{"award-number":["EQU202103012571"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Toxoplasmosis is caused by <jats:italic>Toxoplasma gondii<\/jats:italic> and in immunocompromised patients it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) is a validated druggable target in <jats:italic>Toxoplasma gondii<\/jats:italic> but the traditional \u2018single target\u2013single drug\u2019 approach has its caveats. Here, we describe two potent inhibitors namely halofuginone (HFG) and a novel ATP mimetic (L95) that bind to <jats:italic>Toxoplasma gondii<\/jats:italic> PRS simultaneously at different neighbouring sites to cover all three of the enzyme substrate subsites. HFG and L95 act as one triple-site inhibitor in tandem and form an unusual ternary complex wherein HFG occupies the 3\u2019-end of tRNA and the L-proline (L-pro) binding sites while L95 occupies the ATP pocket. These inhibitors exhibit nanomolar IC<jats:sub>50<\/jats:sub> and EC<jats:sub>50<\/jats:sub> values independently, and when given together reveal an additive mode of action in parasite inhibition assays. This work validates a novel approach and lays a structural framework for further drug development based on simultaneous targeting of multiple pockets to inhibit druggable proteins.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010363","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T17:47:33Z","timestamp":1648230453000},"page":"e1010363","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug 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