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.; Jami, R.; Marinos, G.; Cabreiro, F.; Dräger, A.; Schindler, M.; Kaleta, C. Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs. Preprints2022, 2022100223. https://doi.org/10.20944/preprints202210.0223.v2
Renz, A.; Hohner, M.; Breitenbach, M.; Josephs-Spaulding, J.; Dürrwald, J.; Best, L.; Jami, R.; Marinos, G.; Cabreiro, F.; 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.v2
Renz, A.; Hohner, M.; Breitenbach, M.; Josephs-Spaulding, J.; Dürrwald, J.; Best, L.; Jami, R.; Marinos, G.; Cabreiro, F.; Dräger, A.; Schindler, M.; Kaleta, C. Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs. Preprints2022, 2022100223. https://doi.org/10.20944/preprints202210.0223.v2
APA Style
Renz, A., Hohner, M., Breitenbach, M., Josephs-Spaulding, J., Dürrwald, J., Best, L., Jami, R., Marinos, G., Cabreiro, F., Dräger, A., Schindler, M., & Kaleta, C. (2023). Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs. Preprints. https://doi.org/10.20944/preprints202210.0223.v2
Chicago/Turabian Style
Renz, A., Michael Schindler and Christoph Kaleta. 2023 "Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs" Preprints. https://doi.org/10.20944/preprints202210.0223.v2
Abstract
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.
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.
Received:
30 November 2023
Commenter:
Andreas Dräger
Commenter's Conflict of Interests:
Author
Comment:
The article now includes new findings after evaluating the drug-candidate phenphormine in Syrian hamster models infected with SARS-CoV-2. Several parts of the text were rewritten to explain aspects of computational modeling and the overall approach better. All models are now available in the BioModels Database in a standardized format and will become publicly accessible after peer review. Additional improvements were performed.
Commenter: Andreas Dräger
Commenter's Conflict of Interests: Author