Renz Alina, Hohner Mirjam, Jami Raphaël, Breitenbach Maximilian, Josephs-Spaulding Jonathan, Dürrwald Johanna, Best Lena, Dulière Victoria, Mialon Chloé, Bader Stefanie M, Marinos Georgios, Leonidou Nantia, Cabreiro Filipe, Pellegrini Marc, Doerflinger Marcel, Rosa-Calatrava Manuel, Pizzorno Andrés, Dräger Andreas, Schindler Michael, Kaleta Christoph
Computational Systems Biology of Infections and Antimicrobial-Resistant Pathogens, Institute for Bioinformatics and Medical Informatics (IBMI), Eberhard Karl University of Tübingen, Tübingen, Germany.
Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.
Commun Biol. 2025 May 23;8(1):791. doi: 10.1038/s42003-025-08148-y.
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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）大流行再次凸显了对广谱抗病毒疗法的迫切需求。我们开发了一种利用单细胞RNA测序（scRNA-Seq）数据的计算工作流程，以评估病毒感染期间的细胞代谢。通过这个工作流程，我们预测了患者细胞维持SARS-CoV-2病毒粒子产生的能力，并发现了支持病毒复制的代谢途径在全组织范围内的诱导。将我们的分析扩展到甲型流感病毒和登革病毒，我们确定了潜在广谱抗病毒治疗的代谢靶点和抑制剂。这些靶点在所有分析病毒的已知相互作用伙伴中高度富集。事实上，二甲双胍，一种烟酰胺腺嘌呤二核苷酸（NADH）：泛醌氧化还原酶抑制剂，抑制了SARS-CoV-2和登革病毒的复制。阿替平A5，阻断琥珀酸脱氢酶，以高选择性指数抑制SARS-CoV-2、登革病毒、呼吸道合胞病毒和甲型流感病毒。在体内，二甲双胍在叙利亚仓鼠模型中显示出对SARS-CoV-2的抗病毒活性。我们的工作确立了宿主代谢作为广谱抗病毒策略的可药物靶点，为大流行防范提供了宝贵的工具。
