摘要：SummaryNovel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal and synthetic dosage lethal (SL/SDL) partners of such altered host genes. Pursuing this disparate antiviral strategy, here we comprehensively analyzed multiplein vitroandin vivobulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL/SDL with altered host genes. The predicted SL/SDL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. We further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming noninfected healthy cells.Graphical abstractDisplay OmittedHighlights•Identified anti-SARS-CoV-2 targets using synthetic lethality from infected datasets•Predicted targets are enriched by infected cell inhibiting genes from CRISPR/Cas9 data•Experimental validation of selected SL targets in siRNA assay from human Caco-2 cells•Predicted targets are made publicly available forin vivotesting and validationDrugs; Virology; Synthetic biology
