Introduction: Despite the development of two mRNA vaccines, there is an urgent unmet need of finding new antiviral strategies. One such potential antiviral strategy is to target the synthetic lethal (SL) partners of transcriptionally altered genes in infected host cells, thereby selectively killing them to halt the infection at its heels (Mast FD, JCB, 2020).

Methods: Here we conduct a first proof-of-concept SL inference approach to predict anti-SARS-CoV-2 targets in a systematic genome-wide manner. This effort capitalizes on our recently published pipeline for inferring clinically relevant SL interactions in cancer (Lee et al, Cell, 2021). Based on the latter, we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict candidate antiviral targets that are SL with altered host genes. Importantly, as our predictions are fine-tuned based on the analysis of patients’ data, they are more likely to be of translational value.

Results: Our key results are twofold:1) The predicted SL-based targets are highly enriched for genes that are reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens to inhibit growth of infected cells. 2) A subset of top predicted 26 genes were experimentally tested in a targeted siRNA screen conducted in both infected and non-infected human Caco-2 cells. Remarkably, as expected given that these targets were predicted to be SL specific with genes upregulated in infected cells, indeed, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming non-infected cells.

Conclusion: In summary, this study is the first to demonstrate the potential of a synthetic lethality approach to identify viral (specifically anti-SARS-CoV-2) targets. Importantly, as both single cell and bulk transcriptomics patients’ data is considered from both infected people and controls, they are more likely to be of clinical relevance. Targeting host genes identified via an SL-based approach is probably more suitable when the infection is at the early stage and host can still tolerate the loss of infected host cells.

Citation Format: Lipika R. Pal, Kuoyuan Cheng, Nishanth Ulhas Nair, Laura Martin-Sancho, Sanju Sinha, Yuan Pu, Laura Riva, Xin Yin, Fiorella Schischlik, Joo Sang Lee, Sumit Chanda, Eytan Ruppin. Identifying and testing cancer-derived synthetic-lethal anti-SARS-CoV-2 targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3583.