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 COVID-19.

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. 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 manifesting gene expression signatures of the potential coronavirus infection mitigation agents. Using this strategy, Vitamin D and Quercetin have been identified as putative COVID-19 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 considerations of their potential utility as COVID-19 pandemic mitigation agents. Quercetin has been identified as one of top-scoring candidate therapeutics in the supercomputer SUMMIT drug-docking screen and Gene Set Enrichment Analyses (GSEA) of expression profiling experiments (EPEs), indicating that highly similar structurally Quercetin, Luteolin, and Eriodictyol could serve as efficient inhibitors of the SARS-CoV-2 infection. GSEA and EPEs identify multiple drugs, smoking, and many disease conditions, including seasonal and pandemic H1N1, that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of Testosterone versus Estradiol impacts on SARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during coronavirus pandemic. Age-associated Vitamin D deficiency may contribute to high mortality of older adults and elderly. 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 COVID-19 pandemic.