Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes

Elisa Molina Molina, Joan Josep Bech-Serra, Eloi Franco-Trepat, Ignasi Jarne, Daniel Perez-Zsolt, Roger Badia, Eva Riveira-Muñoz, Edurne Garcia-Vidal, Lluís Revilla, Sandra Franco, Ferran Tarrés-Freixas, Núria Roca, Gerardo Ceada, Karl Kochanowski, Dàlia Raïch-Regué, Itziar Erkizia, Rytis Boreika, Antoni E. Bordoy, Laia Soler, Sonia Guil, Jorge Carrillo, Julià Blanco, Miguel Ángel Martínez, Roger Paredes, Alejandro Losada, Pablo Aviles, Carmen Cuevas, Júlia Vergara-Alert, Joaquim Segalés, Bonaventura Clotet, Ester Ballana, Carolina Torre and Nuria Izquierdo-Useros ()
Additional contact information
Elisa Molina Molina: Universitat Autònoma de Barcelona (UAB)
Joan Josep Bech-Serra: Josep Carreras Leukaemia Research Institute (IJC)
Eloi Franco-Trepat: Universitat Autònoma de Barcelona (UAB)
Ignasi Jarne: Josep Carreras Leukaemia Research Institute (IJC)
Daniel Perez-Zsolt: Universitat Autònoma de Barcelona (UAB)
Roger Badia: Universitat Autònoma de Barcelona (UAB)
Eva Riveira-Muñoz: Universitat Autònoma de Barcelona (UAB)
Edurne Garcia-Vidal: Universitat Autònoma de Barcelona (UAB)
Lluís Revilla: Universitat Autònoma de Barcelona (UAB)
Sandra Franco: Universitat Autònoma de Barcelona (UAB)
Ferran Tarrés-Freixas: Campus de la Universitat Autònoma de Barcelona (UAB)
Núria Roca: Campus de la Universitat Autònoma de Barcelona (UAB)
Gerardo Ceada: Campus de la Universitat Autònoma de Barcelona (UAB)
Karl Kochanowski: Campus de la Universitat Autònoma de Barcelona (UAB)
Dàlia Raïch-Regué: Universitat Autònoma de Barcelona (UAB)
Itziar Erkizia: Universitat Autònoma de Barcelona (UAB)
Rytis Boreika: Universitat Autònoma de Barcelona (UAB)
Antoni E. Bordoy: Germans Trias i Pujol Research Institute and Hospital (IGTP)
Laia Soler: Germans Trias i Pujol Research Institute and Hospital (IGTP)
Sonia Guil: Josep Carreras Leukaemia Research Institute (IJC)
Jorge Carrillo: Universitat Autònoma de Barcelona (UAB)
Julià Blanco: Universitat Autònoma de Barcelona (UAB)
Miguel Ángel Martínez: Universitat Autònoma de Barcelona (UAB)
Roger Paredes: Universitat Autònoma de Barcelona (UAB)
Alejandro Losada: Colmenar Viejo
Pablo Aviles: Colmenar Viejo
Carmen Cuevas: Colmenar Viejo
Júlia Vergara-Alert: Campus de la Universitat Autònoma de Barcelona (UAB)
Joaquim Segalés: Campus de la Universitat Autònoma de Barcelona (UAB)
Bonaventura Clotet: Universitat Autònoma de Barcelona (UAB)
Ester Ballana: Universitat Autònoma de Barcelona (UAB)
Carolina Torre: Josep Carreras Leukaemia Research Institute (IJC)
Nuria Izquierdo-Useros: Universitat Autònoma de Barcelona (UAB)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Plitidepsin is an antitumoral compound safe for treating COVID-19 that targets the translation elongation factor eEF1A. Here we detect that plitidepsin decreases de novo cap-dependent translation of SARS-CoV-2 and non-viral RNAs but affects less than 13% of the host proteome, thus preserving cellular viability. In response to plitidepsin, cells upregulate EIF2AK3 and proteins that reduce translation, but also proteins that support proteostasis via ribosome synthesis and cap-independent translation by eIF4G2 and IGF2BP2. While plitidepsin inhibits cap- or internal ribosome entry sites (IRES)-mediated translation, its impact on N6-methyladenosine (m6A) translation is limited. In agreement, plitidepsin blocks members of Coronaviridae, Flaviviridae, Pneumoviridae and Herpesviridae families. Yet, it fails to inhibit retroviruses that exploit m6A synthesis routes and are blocked by drugs targeting IGF2BP2 m6A reader. By deciphering the molecular fingerprint of cells treated with therapies targeting translation we identify a rational approach to select broad-spectrum antivirals with potential to counteract future pandemic viruses.

Date: 2025
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DOI: 10.1038/s41467-025-56151-y

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