Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses
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.
Authors
- Alina Renz (ORCID: https://orcid.org/0000-0003-3851-9978)
- Michael Schindler (ORCID: https://orcid.org/0000-0001-8989-5813)
- Marcel Doerflinger (ORCID: https://orcid.org/0000-0001-9159-3021)
- Lena Best (ORCID: https://orcid.org/0000-0003-2772-153X)
- Raphaël Jami
- Victoria Dulière
- Γεώργιος Μαρίνος (ORCID: https://orcid.org/0000-0002-6443-7696)
- Maximilian Breitenbach
- Johanna Dürrwald
- Filipe Cabreiro (ORCID: https://orcid.org/0000-0002-3696-4843)
- Manuel Rosa‐Calatrava (ORCID: https://orcid.org/0000-0002-7559-9527)
- Mirjam Hohner
- Nantia Leonidou (ORCID: https://orcid.org/0000-0002-0248-6679)
- Marc Pellegrini (ORCID: https://orcid.org/0000-0003-3627-3126)
- Andreas Dräger (ORCID: https://orcid.org/0000-0002-1240-5553)
- Jonathan Josephs‐Spaulding (ORCID: https://orcid.org/0000-0001-9828-0685)
- Christoph Kaleta (ORCID: https://orcid.org/0000-0001-8004-9514)
- Stefanie M. Bader (ORCID: https://orcid.org/0000-0002-7901-9833)
- Andrés Pizzorno (ORCID: https://orcid.org/0000-0002-0918-6804)
- Chloé Mialon
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Cologne (DE)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Christian-Albrechts-Universität zu Kiel (DE)
- German Center for Infection Research (DE)
- University Children's Hospital Tübingen (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Institute of Medical Microbiology and Hygiene (DE)
- Centre International de Recherche en Infectiologie (FR)
- Martin Luther University Halle-Wittenberg (DE)
- University of Glasgow (GB)
- University of Tübingen (DE)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1038/s42003-025-08148-y
- Citations
- 2
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- Deutsches Zentrum für Infektionsforschung
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- German Network for Bioinformatics Infrastructure