2. Academic Validation
  3. Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes

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

  • Nat Commun. 2025 Feb 7;16(1):1087. doi: 10.1038/s41467-025-56151-y.
Elisa Molina Molina 1,  Joan Josep Bech-Serra 2 3,  Eloi Franco-Trepat 1,  Ignasi Jarne 2 3,  Daniel Perez-Zsolt 1,  Roger Badia 1,  Eva Riveira-Muñoz 1,  Edurne Garcia-Vidal 1,  Lluís Revilla 1,  Sandra Franco 1,  Ferran Tarrés-Freixas 4 5 6,  Núria Roca 4 5,  Gerardo Ceada 4 5,  Karl Kochanowski 4 5,  Dàlia Raïch-Regué 1,  Itziar Erkizia 1,  Rytis Boreika 1,  Antoni E Bordoy 7,  Laia Soler 7,  Sonia Guil 3,  Jorge Carrillo 1 8,  Julià Blanco 1 6 8,  Miguel Ángel Martínez 1,  Roger Paredes 1 8 9 10,  Alejandro Losada 11,  Pablo Aviles 11,  Carmen Cuevas 11,  Júlia Vergara-Alert 4 5,  Joaquim Segalés 4 12,  Bonaventura Clotet 1 6 8,  Ester Ballana 1 8,  Carolina de la Torre 2 3,  Nuria Izquierdo-Useros 13 14
Affiliations

Affiliations

  • 1 IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB), Badalona, Spain.
  • 2 Proteomics Unit, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain.
  • 3 Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain.
  • 4 Unitat mixta d'investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Bellaterra, Catalonia, Spain.
  • 5 IRTA, Animal Health, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB, Bellaterra, Catalonia, Spain.
  • 6 University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.
  • 7 Microbiology Department, Germans Trias i Pujol Research Institute and Hospital (IGTP), Badalona, Spain.
  • 8 CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain.
  • 9 Department of Infectious Diseases, Hospital Germans Trias i Pujol, Badalona, Catalonia, Spain.
  • 10 Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 11 PharmaMar S.A, Colmenar Viejo, Madrid, Spain.
  • 12 Departament de Sanitat i Anatomia Animals, Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
  • 13 IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB), Badalona, Spain. [email protected].
  • 14 CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain. [email protected].
PMID: 39920115 DOI: 10.1038/s41467-025-56151-y
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.

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