Key result
Structure-guided optimization of a dual RSV/hCoV-229E small-molecule inhibitor led to the discovery of a sub-micromolar RSV entry inhibitor, a dual inhibitor, and a highly potent hCoV-229E compound.
Why the study?
There is a lack of efficient, FDA-approved small-molecule drugs targeting viral pathogens such as RSV and hCoV-229E to prevent severe acute respiratory disease through early inhibition of viral entry.
Structure-guided optimization yielded novel, highly potent small-molecule inhibitors targeting the entry stage of RSV and hCoV-229E.
Answers are grounded in this paper and cite their sources.
No practice change for respiratory viruses; leaves open optimization of dual entry inhibitors in preclinical models.
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. • Structure-guided hit-optimization of a dual RSV/hCoV-229E inhibitor. • Differently selective inhibitors for subsequent optimization endeavors. • Valuable SAR insights for all three inhibitor types (RSV/hCoV-229E selective & dual).
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Karhan et al. (2025) studied RSV and hCoV-229E infection. Small-molecule inhibitors was evaluated on Inhibitory activity, cell viability, selectivity, solubility and metabolic stability. Structure-guided optimization of a dual RSV/hCoV-229E small-molecule inhibitor led to the discovery of a sub-micromolar RSV entry inhibitor, a dual inhibitor, and a highly potent hCoV-229E compound.
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