Respiratory viral infections are a major cause of morbidity and mortality worldwide. The COVID-19 pandemic has evidenced the need for broad-spectrum antivirals and improved preclinical models that more accurately recapitulate human respiratory disease. These new strategies should also involve the search for drug targets in the infected cell that hamper the development of resistance and of potential efficacy against diverse viruses. Since many viruses reprogram cellular metabolism to support viral replication, we performed a comparative analysis of inhibitors targeting the PI3K/AKT/mTOR pathway, central to virus-induced metabolic adaptations, using MRC5 lung fibroblasts and Huh7 hepatoma cells. HCoV-229E infection in MRC5 cells caused the expected shift in the energy metabolism but the inhibitors had markedly different effects on the metabolic profile and antiviral activity in these two cell lines. Dichloroacetate (DCA), a clinically approved inhibitor of aerobic glycolysis, showed antiviral activity against HCoV-229E in MRC5 cells, but not in Huh7 cells, underscoring that the screening model is more critical than previously assumed. We further tested DCA in polarized human small airway epithelial cells cultured in air–liquid interface, a 3D model that mimics the human respiratory tract. DCA reduced the viral progeny of HCoV-229E, SARS-CoV-2, and respiratory syncytial virus by 2–3 orders of magnitude, even when administered after infection was established. Our work reinforces the need for advanced human preclinical screening models to identify antivirals that target host metabolic pathways frequently hijacked by respiratory viruses, and establishes DCA as a proof-of-concept candidate.

Respiratory viral infections are a major cause of morbidity and mortality worldwide. The COVID-19 pandemic has highlighted the lack of drugs for fighting emerging viruses and the need for preclinical screening models that better recapitulate human disease. These new strategies should also involve the search for drug targets in the infected cell to hamper the development of resistance and of potential antiviral effect on diverse viruses. Since viruses reprogram cellular metabolism for viral progeny, we performed a comparative analysis of PI3K/AKT/mTOR pathway inhibitors, involved in the virus-induced metabolic adaptations, using MRC5 lung fibroblasts and Huh7 hepatoma cells. We demonstrate that infection of MRC5 cells with HCoV-229E caused the expected shift in the energy metabolism but the inhibitors had markedly different effects on the metabolic profile and antiviral activity in the two cell lines. Thus, dichloroacetate (DCA) had antiviral activity against HCoV-229E in MRC5 but not in Huh7 cells, suggesting that the screening model is more critical than previously assumed. DCA was tested in polarized alveolar epithelia in air-liquid interface, an experimental 3D model considered an innovative tool for studying respiratory infections. DCA was effective against the respiratory viruses HCoV-229E, SARS-CoV-2 and respiratory syncytial virus, even when applied after infection had been established. We conclude that a cellular metabolic pathway commonly hijacked by viruses constitutes a viable therapeutic target for three respiratory viruses that have major impacts on human health and that drug repositioning is a strategic approach to fight emerging pandemics.