Harnessing Powers of Genomics to Build Molecular Maps of Coronavirus Targets in Human Cells: A Guide for Existing Drug Repurposing and Experimental Studies Identifying Candidate Therapeutics to Mitigate the Pandemic

Coronavirus pandemic 2020 caused by the newly emerged SARS-CoV-2 virus is rapidly spreading around the glove and entering the most dangerous acute phase of its evolution in the United States. Recent progress in defining genetic and molecular determinants mediating the SARS-CoV-2 entry into human cells (Walls et al., 2020) should facilitate development of targeted therapeutics and efficient vaccines. Here, human genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomics-guided maps of up-stream regulatory elements, their expression and functions in human body, including pathophysiologically-relevant cell types. Genes acting as repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1) were then employed to identify existing drugs that manifest gene expression signatures of the potential coronavirus infection mitigation agents. Using this strategy, Vitamin D and Quercetin have been identified as putative pandemic mitigation agents. Gene expression profiles of Vitamin D and Quercetin activities and their established safety records as over-the-counter medicinal substances suggest that they may represent viable candidates for further assessment and considerations of their potential utility as coronavirus pandemic mitigation agents. Notably, gene set enrichment analyses and expression profiling experiments identify multiple drugs, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of Testosterone versus Estradiol impacts on SCARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during coronavirus pandemic. Observations reported in this contribution are intended to facilitate follow-up targeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically-viable interventions to combat the pandemic.