Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs

Alina Renz; Mirjam Hohner; Maximilian Breitenbach; Jonathan Josephs-Spaulding; Johanna Dürrwald; Lena Best; Victoria Dulière; Chloé Mialon; Stefanie M. Bader; Raphaël Jami; Georgios Marinos; Nantia Leonidou; Filipe Cabreiro; Marc Pellegrini; Marcel Doerflinger; Manuel Rosa-Calatrava; Andrés Pizzorno; Andreas Dräger; Michael Schindler; Christoph Kaleta

doi:10.20944/preprints202210.0223.v3

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preprints.org > biology and life sciences > virology > doi: 10.20944/preprints202210.0223.v3

Preprint Article Version 3 Preserved in Portico This version is not peer-reviewed

Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs

Alina Renz

Mirjam Hohner

Maximilian Breitenbach

Jonathan Josephs-Spaulding

Manuel Rosa-Calatrava

^* ,

^* ,

Version 1 : Received: 14 October 2022 / Approved: 17 October 2022 / Online: 17 October 2022 (03:42:37 CEST)
Version 2 : Received: 30 November 2023 / Approved: 30 November 2023 / Online: 30 November 2023 (16:08:09 CET)
Version 3 : Received: 22 March 2024 / Approved: 22 March 2024 / Online: 22 March 2024 (16:46:59 CET)

How to cite: Renz, A.; Hohner, M.; Breitenbach, M.; Josephs-Spaulding, J.; Dürrwald, J.; Best, L.; Dulière, V.; Mialon, C.; Bader, S.M.; Jami, R.; Marinos, G.; Leonidou, N.; Cabreiro, F.; Pellegrini, M.; Doerflinger, M.; Rosa-Calatrava, M.; Pizzorno, A.; Dräger, A.; Schindler, M.; Kaleta, C. Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs. Preprints 2022, 2022100223. https://doi.org/10.20944/preprints202210.0223.v3 Renz, A.; Hohner, M.; Breitenbach, M.; Josephs-Spaulding, J.; Dürrwald, J.; Best, L.; Dulière, V.; Mialon, C.; Bader, S.M.; Jami, R.; Marinos, G.; Leonidou, N.; Cabreiro, F.; Pellegrini, M.; Doerflinger, M.; Rosa-Calatrava, M.; Pizzorno, A.; Dräger, A.; Schindler, M.; Kaleta, C. Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs. Preprints 2022, 2022100223. https://doi.org/10.20944/preprints202210.0223.v3

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MDPI and ACS Style

Renz, A.; Hohner, M.; Breitenbach, M.; Josephs-Spaulding, J.; Dürrwald, J.; Best, L.; Dulière, V.; Mialon, C.; Bader, S.M.; Jami, R.; Marinos, G.; Leonidou, N.; Cabreiro, F.; Pellegrini, M.; Doerflinger, M.; Rosa-Calatrava, M.; Pizzorno, A.; Dräger, A.; Schindler, M.; Kaleta, C. Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs. Preprints 2022, 2022100223. https://doi.org/10.20944/preprints202210.0223.v3

APA Style

Renz, A., Hohner, M., Breitenbach, M., Josephs-Spaulding, J., Dürrwald, J., Best, L., Dulière, V., Mialon, C., Bader, S.M., Jami, R., Marinos, G., Leonidou, N., Cabreiro, F., Pellegrini, M., Doerflinger, M., Rosa-Calatrava, M., Pizzorno, A., Dräger, A., Schindler, M., & Kaleta, C. (2024). Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs. Preprints. https://doi.org/10.20944/preprints202210.0223.v3

Chicago/Turabian Style

Renz, A., Michael Schindler and Christoph Kaleta. 2024 "Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs" Preprints. https://doi.org/10.20944/preprints202210.0223.v3

Abstract

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-45 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.

Keywords

Drug discovery; Systems biology; SARS-CoV-2; Dengue; Influenza A; RSV; cell viability analysis; antivirals; in vitro validation; in vivo validation

Subject

Biology and Life Sciences, Virology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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