Unlocking the Antiviral Arsenal: Multiparametric Optimization of Small-Molecule Inhibitors against RSV and hCoV-229E

Acute respiratory diseases in humans can be caused by various viral pathogens such as respiratory syncytial virus (RSV), human coronavirus 229E (hCoV-229E), and severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2). To prevent severe cases by an early treatment, one effective strategy is to inhibit viral infection at the entry stage of the replication cycle. However, there is a lack of efficient, FDA-approved small molecule drugs targeting these pathogens. Previously, we identified two dual RSV/hCoV-229E small molecule inhibitors with activity in the single-digit micromolar range. In this study, we focused on optimizing the more promising starting point using a multiparametric hit optimization approach. Here, we present the results, including valuable insights into the structure activity relationship (SAR), and report the discovery of a submicromolar RSV entry inhibitor and a highly potent compound against hCoV-229E.