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In addition, the globally distributed MaAv lymphocytic choriomeningitis virus (LCMV) is an underrecognized human pathogen of clinical significance especially in congenital infections and LCMV poses a serious risk for immunocompromised individuals. There are no FDA-approved MaAv vaccines or antivirals and current anti-MaAv therapy is limited to an off-label use of ribavirin whose efficacy remains controversial. This highlights an urgent unmet need for developing antivirals against human pathogenic MaAv. Halofuginone (HF), a derivative of the natural alkaloid febrifugine, has been shown to exhibit antiviral activity against several RNA viruses. Here, we present evidence that HF exhibits a potent dose-dependent antiviral activity against LCMV, and the hemorrhagic fever causing MaAv LASV and JUNV. HF binds to the bifunctional enzyme glutamyl-prolyl-tRNA synthetase 1 (EPRS1) and specifically inhibits its prolyl-tRNA synthetase (PRS) activity, resulting in translation inhibition via the amino acid starvation (AAS) response with preferential impact on proline-rich proteins. HF anti-LCMV activity was prevented by the addition of exogenous proline supporting that inhibition of PRS activity plays a critical role on the anti-MaAv activity of HF. We found that HF did not affect LCMV cell entry, modestly (twofold) reduced the activity of the virus ribonucleoprotein (vRNP) but strongly inhibited (&gt;90%) Z budding activity, a process involving the Z proline-rich late domain motifs.<\/jats:p>","DOI":"10.64898\/2026.01.15.699610","type":"posted-content","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T03:20:14Z","timestamp":1768533614000},"source":"Crossref","is-referenced-by-count":1,"title":["Prolyl tRNA Synthetase Is Required for Mammarenavirus Multiplication"],"prefix":"10.64898","author":[{"given":"Haydar","family":"Witwit","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Ibanez","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel","family":"Jackson","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, TX 78227, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruby","family":"Escobedo","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, TX 78227, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Cubitt","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roaa","family":"Khafaji","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel Y.","family":"Sattler","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Martinez-Sobrido","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, TX 78227, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"de la Torre","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020606364878000_2026.01.15.699610v1.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1008811"},{"key":"2026020606364878000_2026.01.15.699610v1.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000388"},{"key":"2026020606364878000_2026.01.15.699610v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/82_2023_263"},{"key":"2026020606364878000_2026.01.15.699610v1.4","unstructured":"Radoshitzky, S.R. ; Buchmeier, M. ; de la Torre, J.C. 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