Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses

Renz, A; Hohner, M; Jami, R; Breitenbach, M; Josephs-Spaulding, J; D&#252;rrwald, J; Best, L; Duli&#232;re, V; Mialon, C; Bader, SM; Marinos, G; Leonidou, N; Cabreiro, F; Pellegrini, M; Doerflinger, M; Rosa-Calatrava, M; Pizzorno, A; Dr&#228;ger, A; Schindler, M; Kaleta, C

Author(s): Renz, A; Hohner, M; Jami, R; Breitenbach, M; Josephs-Spaulding, J; Dürrwald, J; Best, L; Dulière, V; Mialon, C; Bader, SM; Marinos, G; Leonidou, N; Cabreiro, F; Pellegrini, M; Doerflinger, M; Rosa-Calatrava, M; Pizzorno, A; Dräger, A; Schindler, M; Kaleta, C;
Details: Publication Year 2025-05-23,Volume 8,Issue #1,Page 791
Journal Title: Communications Biology
Publication Type: May 23
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.
Publisher: Springer Nature
Keywords: *Antiviral Agents/pharmacology; Animals; *SARS-CoV-2/drug effects/physiology; Humans; *Phenformin/pharmacology/therapeutic use; COVID-19/virology/metabolism; Virus Replication/drug effects; *COVID-19 Drug Treatment; Cricetinae; *RNA Viruses/drug effects; Influenza A virus/drug effects; Mesocricetus
Research Division(s): Infection and Global Health
PubMed ID: 40410544
Publisher's Version: https://doi.org/10.1038/s42003-025-08148-y
Open Access at Publisher's Site: https://doi.org/10.1038/s42003-025-08148-y
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-29 02:03:17

Last Modified: 2025-05-29 02:08:05