Respiratory viral infections are a significant cause of morbidity and mortality worldwide. COVID-19 pandemic highlighted the lack of chemotherapeutical tools to fight emerging viruses and the need to focus on preclinical models that better recapitulate the human disease. We performed a comparative analysis of inhibitors of the PI3K/AKT/mTOR pathway, involved in the virus-induced metabolic reprogramming, since strategies aimed to cellular targets should serve to combat diverse viruses and hamper the development of resistance. Tests were performed in two human cell lines, MRC5 lung fibroblasts and Huh7 hepatoma cells, and showed that the inhibitors had markedly different effects on energy metabolism and in antiviral activity. Thus, dichloroacetate (DCA) had a potent antiviral activity against HCoV-229E in MRC5 but not in Huh7 cells, implying that the screening model appears to be more critical than previously assumed. DCA was then tested in polarized human alveolar epithelia in air-liquid interface, a 3D model to study respiratory infections. DCA reduced the viral progeny of HCoV-229E, SARS-CoV-2 and the respiratory syncytial virus by 2–3 orders of magnitude, being effective even when applied once infection had been established. Although DCA has previously been shown to be effective against other viruses, suggesting it could be a broad-spectrum antiviral, our experiments reinforce the need to use physiologically appropriate disease models to screen antiviral compounds.

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