Short communicationNovel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen

•A high throughput replicon-based screen was combined with live virus triaging assays to identify inhibitors of RSV.•Several novel diversity-oriented synthesis-derived chemical scaffolds that inhibit RSV were identified.•These compounds may provide attractive starting points for lead optimization campaigns for RSV therapeutics.

Respiratory syncytial virus (RSV) infections affect millions of children and adults every year. Despite the significant disease burden, there are currently no safe and effective vaccines or therapeutics. We employed a replicon-based high throughput screen combined with live-virus triaging assays to identify three novel diversity-oriented synthesis-derived scaffolds with activity against RSV. One of these small molecules is shown to target the RSV polymerase (L protein) to inhibit viral replication and transcription; the mechanisms of action of the other small molecules are currently unknown. The compounds described herein may provide attractive inhibitors for lead optimization campaigns.