Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

Novel 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 multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL/SDLwith 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.

Automated summary

This article proposes a novel strategy to identify drug targets and treatments for the COVID-19 pandemic by analyzing the altered gene expression of virus-infected host cells. The study finds that these targets can effectively inhibit viral replication without harming healthy cells.