Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes
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 preservin...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56151-y |
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| author | 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 de la Torre Nuria Izquierdo-Useros |
| author_facet | 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 de la Torre Nuria Izquierdo-Useros |
| author_sort | Elisa Molina Molina |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8f85394d674b4daf93c359016ba55f79 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8f85394d674b4daf93c359016ba55f792025-02-09T12:44:57ZengNature PortfolioNature Communications2041-17232025-02-0116111710.1038/s41467-025-56151-yTargeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routesElisa Molina Molina0Joan Josep Bech-Serra1Eloi Franco-Trepat2Ignasi Jarne3Daniel Perez-Zsolt4Roger Badia5Eva Riveira-Muñoz6Edurne Garcia-Vidal7Lluís Revilla8Sandra Franco9Ferran Tarrés-Freixas10Núria Roca11Gerardo Ceada12Karl Kochanowski13Dàlia Raïch-Regué14Itziar Erkizia15Rytis Boreika16Antoni E. Bordoy17Laia Soler18Sonia Guil19Jorge Carrillo20Julià Blanco21Miguel Ángel Martínez22Roger Paredes23Alejandro Losada24Pablo Aviles25Carmen Cuevas26Júlia Vergara-Alert27Joaquim Segalés28Bonaventura Clotet29Ester Ballana30Carolina de la Torre31Nuria Izquierdo-Useros32IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)Proteomics Unit, Josep Carreras Leukaemia Research Institute (IJC)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)Proteomics Unit, Josep Carreras Leukaemia Research Institute (IJC)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)Unitat mixta d’investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB)Unitat mixta d’investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB)Unitat mixta d’investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB)Unitat mixta d’investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)Microbiology Department, Germans Trias i Pujol Research Institute and Hospital (IGTP)Microbiology Department, Germans Trias i Pujol Research Institute and Hospital (IGTP)Josep Carreras Leukaemia Research Institute (IJC)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)PharmaMar S.A, Colmenar ViejoPharmaMar S.A, Colmenar ViejoPharmaMar S.A, Colmenar ViejoUnitat mixta d’investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB)Unitat mixta d’investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)Proteomics Unit, Josep Carreras Leukaemia Research Institute (IJC)IrsiCaixa, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB)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.https://doi.org/10.1038/s41467-025-56151-y |
| spellingShingle | 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 de la Torre Nuria Izquierdo-Useros Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes Nature Communications |
| title | Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes |
| title_full | Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes |
| title_fullStr | Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes |
| title_full_unstemmed | Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes |
| title_short | Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes |
| title_sort | targeting eef1a reprograms translation and uncovers broad spectrum antivirals against cap or m6a protein synthesis routes |
| url | https://doi.org/10.1038/s41467-025-56151-y |
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