Genomics-guided molecular maps of coronavirus targets in human cells: a path toward the repurposing of existing drugs to mitigate the pandemic

Abstract

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 could be repurposed to mitigate the coronavirus infection. Present analyses identify Vitamin D and Quercetin as promising 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 as coronavirus pandemic mitigation agents. Notably, gene set enrichment analyses and expression profiling experiments identify multiple drugs, most notably testosterone, dexamethasone, and doxorubicin, 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.

References in corpus (4)

• Identification and characterization of unique to human regulatory sequences in embryonic stem cells reveal associations with transposable elements, distal enhancers, non-coding RNA, and DNA methylation-driven mechanisms of genome editing
• Role of distal enhancers in shaping 3D-folding patterns and defining human-specific features of interphase chromatin architecture in embryonic stem cells
• Phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via two mechanistically distinct pathways of creation of divergent regulatory DNA sequences
• Analysis of evolutionary origins of genomic loci harboring 59,732 candidate human-specific regulatory sequences identifies genetic divergence patterns during evolution of Great Apes