Human airway organoids as a high-throughput screening platform for antiviral natural products discovery

ABSTRACT Antiviral drug discovery for respiratory viruses is hindered by the lack of scalable physiologically relevant systems. Here, we report the first high-throughput screen of 764 natural plant extracts against respiratory syncytial virus (RSV) using human primary airway organoids as a relevant model. A parallel screen conducted in A549 cells allowed the identification of 70 extracts with organoid-specific antiviral activity from which 45 active phytocompounds were purified. We identified early- and late-acting antiviral compounds and demonstrated a polarization-dependent activity for some of them. Collectively, our results establish the use of airway organoids as a scalable first-line platform for high-throughput antiviral discovery and exploit the plant-derived chemical space as an underexplored source of RSV inhibitors.