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.