Integrated biological and metabolomic profiling to identify novel Respiratory Syncytial VIRUS (RSV) antiviral natural products

Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis in children, with no effective treatment available [ 1 ]. Natural products, long recognized as a cornerstone of drug discovery, offer significant potential to address this unmet need. To identify new antiviral molecules, we screened 800 plant natural extracts (NEs) prepared from the Pierre-Fabre Laboratoires (PFL) [ 2 ] using a fluorescence cell-based assay. NEs exhibiting antiviral activity in RSV-infected cells while maintaining>75% cell viability were further confirmed in an apical-out airway organoid model. Simultaneously, extracts were systematically characterized through integrated UHPLC-HRMS 2 metabolite profiling analysis. We prioritized NEs with fewer reported compounds and excluded those containing known antivirals using metabolomics and annotation tools. This approach led to the identification of four promising NEs. The active compounds were isolated by high-resolution semi-prep. HPLC chromatography combining the gradient transfer and dry load injection [ 3 ]. Structure elucidation was performed by UV, HRMS, and NMR. EC50 values of pure compounds were comparable to or exceeding those of the reference compound, ribavirin. The identified molecules encompass a diverse range of chemical classes, including chalcones, isoquinoline alkaloids, indole alkaloids, and stilbene derivatives. Further experiments will elucidate their mechanism of action and the stage in RSV. Subsequently, the most promising molecules will be tested in ex vivo reconstituted human airway epithelial tissue to further assess their therapeutic potential in more physiological conditions. This study highlights the effectiveness of our screening workflow in identifying novel RSV inhibitors and advancing antiviral drug discovery. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany