A utility of air–liquid interface cultured airway epithelium for the development of antiviral agents: translation beyond biology

The development of antiviral therapies for respiratory viruses continues to be a major unmet clinical need. One of the key challenges in antiviral drug discovery is the identification of preclinical systems that faithfully reproduce essential features of the human airway while retaining clinical relevance. Primary human airway epithelial cells cultured under air-liquid interface (ALI) conditions provide a differentiated and polarized epithelial model with functional cilia, mucus production, barrier formation, and innate antiviral responses. Importantly, patterns of viral replication and host responses observed in ALI cultures often parallel findings from human infection studies and controlled viral challenge models. Beyond mechanistic studies of virus-epithelium interactions, ALI platforms are increasingly applied to translational decision-making, including dose prediction, biomarker assessment, alignment of preclinical and clinical endpoints, and estimation of clinical trial design parameters. Clinical experience with antiviral agents such as an RSV polymerase inhibitor (PC786) and a narrow-spectrum kinase inhibitor (RV568) further supports the translational utility of these systems. This review summarises the biological rationale for ALI airway models and highlights their expanding role in bridging mechanistic research with early clinical development.