{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:04:33Z","timestamp":1791072273590,"version":"4.1.0"},"reference-count":78,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Eukaryot Cell"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Human African trypanosomiasis (HAT) is an important public health threat in sub-Saharan Africa. Current drugs are unsatisfactory, and new drugs are being sought. Few validated enzyme targets are available to support drug discovery efforts, so our goal was to obtain essentiality data on genes with proven utility as drug targets. Aminoacyl-tRNA synthetases (aaRSs) are known drug targets for bacterial and fungal pathogens and are required for protein synthesis. Here we survey the essentiality of eight\n            <jats:named-content content-type=\"genus-species\">Trypanosoma brucei<\/jats:named-content>\n            aaRSs by RNA interference (RNAi) gene expression knockdown, covering an enzyme from each major aaRS class: valyl-tRNA synthetase (ValRS) (class Ia), tryptophanyl-tRNA synthetase (TrpRS-1) (class Ib), arginyl-tRNA synthetase (ArgRS) (class Ic), glutamyl-tRNA synthetase (GluRS) (class 1c), threonyl-tRNA synthetase (ThrRS) (class IIa), asparaginyl-tRNA synthetase (AsnRS) (class IIb), and phenylalanyl-tRNA synthetase (\u03b1 and \u03b2) (PheRS) (class IIc). Knockdown of mRNA encoding these enzymes in\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            mammalian stage parasites showed that all were essential for parasite growth and survival\n            <jats:italic>in vitro<\/jats:italic>\n            . The reduced expression resulted in growth, morphological, cell cycle, and DNA content abnormalities. ThrRS was characterized in greater detail, showing that the purified recombinant enzyme displayed ThrRS activity and that the protein localized to both the cytosol and mitochondrion. Borrelidin, a known inhibitor of ThrRS, was an inhibitor of\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            ThrRS and showed antitrypanosomal activity. The data show that aaRSs are essential for\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            survival and are likely to be excellent targets for drug discovery efforts.\n          <\/jats:p>","DOI":"10.1128\/ec.00017-14","type":"journal-article","created":{"date-parts":[[2014,2,22]],"date-time":"2014-02-22T06:30:09Z","timestamp":1393050609000},"page":"504-516","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":27,"title":["Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei"],"prefix":"10.1128","volume":"13","author":[{"given":"Savitha","family":"Kalidas","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Cestari","sequence":"additional","affiliation":[{"name":"Seattle Biomedical Research Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Severine","family":"Monnerat","sequence":"additional","affiliation":[{"name":"Seattle Biomedical Research Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandesh","family":"Regmi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Hasle","sequence":"additional","affiliation":[{"name":"Seattle Biomedical Research Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Labaied","sequence":"additional","affiliation":[{"name":"Seattle Biomedical Research Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn","family":"Parsons","sequence":"additional","affiliation":[{"name":"Seattle Biomedical Research Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Stuart","sequence":"additional","affiliation":[{"name":"Seattle Biomedical Research Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, 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