Journal Article

Prolyl tRNA Synthetase Is Required for Mammarenavirus Multiplication

Ibanez, Pablo, Escobedo, Ruby, Martinez-Sobrido, Luis, de la Torre, Juan, Cubitt, Beatrice, Witwit, Haydar, Zhou, Ruifeng, Sattler, Rachel, Jackson, Nathaniel, Khafaji, Roaa

2026

Overview

Several mammarenaviruses (MaAv), chiefly Lassa virus (LASV) in Western Africa and Junin virus (JUNV) in the Argentinean Pampas, cause severe disease in humans and pose important public health problems in their endemic regions. 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 potent dose-dependent antiviral activity against LCMV, and against 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 in 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 (>90%) Z budding activity, a process involving the Z proline-rich late domain motifs.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Amino acid starvation / Amino acids / Amino Acyl-tRNA Synthetases - genetics / Amino Acyl-tRNA Synthetases - metabolism / Analysis / Animals / Antiviral activity / Antiviral agents / Antiviral Agents - pharmacology / Antiviral drugs / Arenaviridae - drug effects / Arenaviridae - physiology / Cell Line / Demographic aspects / Diagnosis / Dosage and administration / Drug approval / Fatalities / Fever / Genetic translation / Health aspects / Hemorrhagic fever / host-directed antivirals / Humans / Immunocompetence / Infection / Infections / Infectious diseases / Junin virus - drug effects / Junin virus - physiology / JUNV / Lassa fever / Lassa virus - drug effects / Lassa virus - physiology / LASV / LCMV / Ligases / Lymphocytic choriomeningitis virus - drug effects / Lymphocytic choriomeningitis virus - physiology / mammarenaviruses / Monoclonal antibodies / Penicillin / Piperidines - pharmacology / Proline / Proline-tRNA ligase / prolyl-tRNA synthetase / Public health / Quinazolinones - pharmacology / Ribavirin / Risk factors / RNA viruses / Transfer RNA / tRNA / Vaccines / Viral vaccines / Virus Replication - drug effects / Viruses