Unlocking the Antiviral Arsenal: Structure-Guided 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 (SARS-CoV-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 a structure-guided optimization approach of the more promising prototype addressing activity, cell viability, selectivity, solubility and metabolic stability. We present valuable insights into the structure–activity relationship (SAR), and report the discovery of a sub micromolar RSV entry inhibitor, a dual RSV/CoV-229E inhibitor and a highly potent compound against hCoV-229E.