Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes
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 (m<sup>6</sup>A) translation is limited. In agreement, plitidepsin blocks members of Coronaviridae, Flaviviridae, Pneumoviridae and Herpesviridae families. Yet, it fails to inhibit retroviruses that exploit m<sup>6</sup>A synthesis routes and are blocked by drugs targeting IGF2BP2 m<sup>6</sup>A 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.
Authors
- Laia Soler (ORCID: https://orcid.org/0009-0000-4122-5079)
- Eloi Franco‐Trepat (ORCID: https://orcid.org/0000-0001-7514-4672)
- Daniel Perez‐Zsolt (ORCID: https://orcid.org/0000-0003-4192-7622)
- Karl Kochanowski (ORCID: https://orcid.org/0000-0002-1884-7694)
- Nuria Izquierdo‐Useros (ORCID: https://orcid.org/0000-0002-1039-1821)
- Alejandro Losada (ORCID: https://orcid.org/0009-0001-2405-878X)
- Eva Riveira‐Muñoz (ORCID: https://orcid.org/0000-0002-6396-1162)
- Ferran Tarrés-Freixas (ORCID: https://orcid.org/0000-0002-1569-0126)
- Itziar Erkizia (ORCID: https://orcid.org/0000-0003-1244-8972)
- Roger Badía (ORCID: https://orcid.org/0000-0003-3982-7577)
- Sandra Franco (ORCID: https://orcid.org/0000-0003-4126-2202)
- Joan Josep Bech‐Serra (ORCID: https://orcid.org/0000-0003-3486-781X)
- Rytis Boreika (ORCID: https://orcid.org/0000-0001-6720-1577)
- Bonaventura Clotet (ORCID: https://orcid.org/0000-0003-3232-4598)
- Gerardo Ceada (ORCID: https://orcid.org/0000-0002-0524-4018)
- Núria Roca (ORCID: https://orcid.org/0009-0009-7743-7458)
- Dàlia Raϊch‐Regué (ORCID: https://orcid.org/0000-0001-7656-5700)
- Antoni E. Bordoy (ORCID: https://orcid.org/0000-0002-1165-542X)
- Edurne García-Vidal (ORCID: https://orcid.org/0000-0003-0698-8710)
- Ester Ballana (ORCID: https://orcid.org/0000-0002-5215-7363)
- Sònia Guil (ORCID: https://orcid.org/0000-0002-2257-3331)
- Joaquím Segalés (ORCID: https://orcid.org/0000-0002-1539-7261)
- Lluís Revilla Sancho (ORCID: https://orcid.org/0000-0001-9747-2570)
- Júlia Vergara‐Alert (ORCID: https://orcid.org/0000-0001-7484-444X)
- Julià Blanco (ORCID: https://orcid.org/0000-0002-2225-0217)
- Jorge Carrillo (ORCID: https://orcid.org/0000-0003-0221-5948)
- Roger Paredes (ORCID: https://orcid.org/0000-0002-6553-691X)
- Ignasi Jarne-Sanz (ORCID: https://orcid.org/0009-0000-7281-4028)
- Miguel Ángel Martı́nez (ORCID: https://orcid.org/0000-0002-6681-4950)
- E. Molina (ORCID: https://orcid.org/0000-0002-3577-0131)
- Carolina de la Torre (ORCID: https://orcid.org/0000-0001-9363-291X)
- Carmen Cuevas (ORCID: https://orcid.org/0000-0002-9116-2405)
- Pablo Avilés
Institutions
- Universitat de Vic - Universitat Central de Catalunya (ES)
- Universitat Autònoma de Barcelona (ES)
- Instituto de Salud Carlos III (ES)
- IrsiCaixa (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Centre de Recerca en Sanitat Animal (ES)
- Centro de Investigación Biomédica en Red (ES)
- PharmaMar (Spain) (ES)
- Center for Global Health (US)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
- Hospital Universitari Germans Trias i Pujol (ES)
- Case Western Reserve University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1038/s41467-025-56151-y
- Citations
- 17
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 13.70