A path-based analysis of infected cell line and COVID-19 patient transcriptome reveals novel potential targets and drugs against SARS-CoV-2

Abstract

Abstract Most transcriptomic studies of SARS-CoV-2 infection have focused on differentially expressedgenes, which do not necessarily reveal the genes mediating the transcriptomic changes. In contrast,exploiting curated biological network, our PathExt tool identifies central genes from thedifferentially active paths mediating global transcriptomic response. Here we apply PathExt tomultiple cell line infection models of SARS-CoV-2 and other viruses, as well as to COVID-19patient-derived PBMCs. The central genes mediating SARS-CoV-2 response in cell lines wereuniquely enriched for ATP metabolic process, G1/S transition, leukocyte activation and migration.In contrast, PBMC response reveals dysregulated cell-cycle processes. In PBMC, the mostfrequently central genes are associated with COVID-19 severity. Importantly, relative todifferential genes, PathExt-identified genes show greater concordance with several benchmarkanti-COVID-19 target gene sets. We propose six novel anti-SARS-CoV-2 targets ADCY2, ADSL,OCRL, TIAM1, PBK, and BUB1, and potential drugs targeting these genes, such as Bemcentinib,Phthalocyanine, and Conivaptan.