Fig. 2: GSEA and target gene expression.

a, Enriched targets and mechanisms of action of potential antiviral compounds were determined through GSEA. GSEA enrichment plots provide the distribution of the enrichment score (green line) across compounds that were annotated to molecular targets, ranked in order of antiviral activities (left to right). Vertical black lines reflect the position of each compound within a specific target class across the ranked dataset, where the leftmost position indicates most potent antiviral activity (red), and the rightmost position indicates inactivity in the HTS screen (blue). Enriched target clusters are shown, including retinoic acid receptor agonists, benzodiazepine receptor inhibitors, aldose reductase agonists, potassium channel agonists, cholesterol inhibitors and antimalarials (P < 0.05, false discovery rate (FDR) q < 0.33). Additional enriched target classes are shown in Extended Data Fig. 2. P values were calculated as indicated in the Methods. b, Chemical epistasis analysis of retinoic acid receptor agonist antiviral activity. Left, Vero E6 cells were treated with 5 μM of the RAR agonist tazarotene and challenged with SARS-CoV-2, and infection was determined as described in Fig. 3. Similarly, Vero E6 cells where pretreated with 5 μM of the RAR antagonist Ro41-5253, either alone or in combination with 5 μM of tazarotene (left). Cellular toxicity was measured by counting cell numbers (right). Data are normalized to the mean of DMSO-treated wells and represent mean ± s.e.m. for n = 3 independent experiments. One-way ANOVA followed by Dunnett post-test. **P ≤ 0.01 and ***P ≤ 0.001.