Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs
Abstract:The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational pipeline using scRNA-Seq data to assess cellular metabolism during viral infection. With this pipeline 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 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..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Preprints.org - (2024) vom: 25. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Renz, Alina [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.20944/preprints202210.0223.v2 |
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| PPN (Katalog-ID): |
preprintsorg037592440 |
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| 520 | |a Abstract:The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational pipeline using scRNA-Seq data to assess cellular metabolism during viral infection. With this pipeline 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 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. | ||
| 700 | 1 | |a Hohner, Mirjam |4 aut | |
| 700 | 1 | |a Breitenbach, Maximilian |4 aut | |
| 700 | 1 | |a Josephs-Spaulding, Jonathan |4 aut | |
| 700 | 1 | |a Dürrwald, Johanna |4 aut | |
| 700 | 1 | |a Best, Lena |0 (orcid)0000-0003-2772-153X |4 aut | |
| 700 | 1 | |a Jami, Raphaël |4 aut | |
| 700 | 1 | |a Marinos, Georgios |0 (orcid)0000-0002-6443-7696 |4 aut | |
| 700 | 1 | |a Cabreiro, Filipe |4 aut | |
| 700 | 1 | |a Dräger, Andreas |0 (orcid)0000-0002-1240-5553 |4 aut | |
| 700 | 1 | |a Schindler, Michael |0 (orcid)0000-0001-8989-5813 |4 aut | |
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