Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses
Abstract The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virio...
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Nature Portfolio
2025-05-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08148-y |
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| author | Alina Renz Mirjam Hohner Raphaël Jami Maximilian Breitenbach Jonathan Josephs-Spaulding Johanna Dürrwald Lena Best Victoria Dulière Chloé Mialon Stefanie M. Bader Georgios Marinos Nantia Leonidou Filipe Cabreiro Marc Pellegrini Marcel Doerflinger Manuel Rosa-Calatrava Andrés Pizzorno Andreas Dräger Michael Schindler Christoph Kaleta |
| author_facet | Alina Renz Mirjam Hohner Raphaël Jami Maximilian Breitenbach Jonathan Josephs-Spaulding Johanna Dürrwald Lena Best Victoria Dulière Chloé Mialon Stefanie M. Bader Georgios Marinos Nantia Leonidou Filipe Cabreiro Marc Pellegrini Marcel Doerflinger Manuel Rosa-Calatrava Andrés Pizzorno Andreas Dräger Michael Schindler Christoph Kaleta |
| author_sort | Alina Renz |
| collection | DOAJ |
| description | Abstract The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A virus with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness. |
| format | Article |
| id | doaj-art-5fc348de31a04dc7ae944f3341da0cf5 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-5fc348de31a04dc7ae944f3341da0cf52025-08-20T02:33:32ZengNature PortfolioCommunications Biology2399-36422025-05-018111910.1038/s42003-025-08148-yMetabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA virusesAlina Renz0Mirjam Hohner1Raphaël Jami2Maximilian Breitenbach3Jonathan Josephs-Spaulding4Johanna Dürrwald5Lena Best6Victoria Dulière7Chloé Mialon8Stefanie M. Bader9Georgios Marinos10Nantia Leonidou11Filipe Cabreiro12Marc Pellegrini13Marcel Doerflinger14Manuel Rosa-Calatrava15Andrés Pizzorno16Andreas Dräger17Michael Schindler18Christoph Kaleta19Computational Systems Biology of Infections and Antimicrobial-Resistant Pathogens, Institute for Bioinformatics and Medical Informatics (IBMI), Eberhard Karl University of TübingenInstitute for Medical Virology and Epidemiology of Viral Diseases, University Hospital TübingenInstitute for Medical Virology and Epidemiology of Viral Diseases, University Hospital TübingenInstitute for Medical Virology and Epidemiology of Viral Diseases, University Hospital TübingenResearch Group Medical Systems Biology, Institute of Experimental Medicine, Christian-Albrechts-University Kiel & University Hospital Schleswig HolsteinInstitute for Medical Virology and Epidemiology of Viral Diseases, University Hospital TübingenResearch Group Medical Systems Biology, Institute of Experimental Medicine, Christian-Albrechts-University Kiel & University Hospital Schleswig HolsteinCIRI, Centre International de Recherche en Infectiologie (Team VirPath), Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de LyonCIRI, Centre International de Recherche en Infectiologie (Team VirPath), Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de LyonDivision of Infectious Diseases and Immune Defense, The Walter and Eliza Hall Institute of Medical ResearchResearch Group Medical Systems Biology, Institute of Experimental Medicine, Christian-Albrechts-University Kiel & University Hospital Schleswig HolsteinComputational Systems Biology of Infections and Antimicrobial-Resistant Pathogens, Institute for Bioinformatics and Medical Informatics (IBMI), Eberhard Karl University of TübingenCologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneDivision of Infectious Diseases and Immune Defense, The Walter and Eliza Hall Institute of Medical ResearchDivision of Infectious Diseases and Immune Defense, The Walter and Eliza Hall Institute of Medical ResearchCIRI, Centre International de Recherche en Infectiologie (Team VirPath), Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de LyonCIRI, Centre International de Recherche en Infectiologie (Team VirPath), Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de LyonComputational Systems Biology of Infections and Antimicrobial-Resistant Pathogens, Institute for Bioinformatics and Medical Informatics (IBMI), Eberhard Karl University of TübingenInstitute for Medical Virology and Epidemiology of Viral Diseases, University Hospital TübingenResearch Group Medical Systems Biology, Institute of Experimental Medicine, Christian-Albrechts-University Kiel & University Hospital Schleswig HolsteinAbstract The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A virus with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness.https://doi.org/10.1038/s42003-025-08148-y |
| spellingShingle | Alina Renz Mirjam Hohner Raphaël Jami Maximilian Breitenbach Jonathan Josephs-Spaulding Johanna Dürrwald Lena Best Victoria Dulière Chloé Mialon Stefanie M. Bader Georgios Marinos Nantia Leonidou Filipe Cabreiro Marc Pellegrini Marcel Doerflinger Manuel Rosa-Calatrava Andrés Pizzorno Andreas Dräger Michael Schindler Christoph Kaleta Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses Communications Biology |
| title | Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses |
| title_full | Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses |
| title_fullStr | Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses |
| title_full_unstemmed | Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses |
| title_short | Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses |
| title_sort | metabolic modeling elucidates phenformin and atpenin a5 as broad spectrum antiviral drugs against rna viruses |
| url | https://doi.org/10.1038/s42003-025-08148-y |
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