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</p><p>Genes
required for SARS-CoV-2 entry into human cells, <i>ACE2</i> and <i>FURIN</i>, were
employed as baits to build genomics-guided molecular maps of up-stream
regulatory elements, their expression and functions in human body, including
pathophysiologically-relevant cell types. Repressors and activators of the <i>ACE2</i> and <i>FURIN</i> genes were identified based on the analyses of gene silencing
and overexpression experiments as well as relevant transgenic mouse models.
Panels of repressors (<i>VDR; GATA5; SFTPC;
HIF1a</i>) and activators (<i>HMGA2; INSIG1</i>)
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 scaffolds
for development of efficient inhibitors of the SARS-CoV-2 infection. In
agreement with this notion, Quercetin alters expression of 98 of 332 (30%) of human
genes encoding protein targets of SARS-CoV-2, thus potentially interfering with
functions of 23 of 27 (85%) of the SARS-CoV-2 viral proteins in human cells. 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.
Of major concern is the ACE2 and FURIN expression in many human cells and
tissues, including immune cells, suggesting that SARS-CoV-2 coronavirus may
infect a broad range of cellular targets in the human body. Infection of immune
cells may cause immunosuppression, long-term persistence of the virus, and
spread of the virus to secondary targets. Present analyses and numerous
observational studies indicate that age-associated Vitamin D deficiency may
contribute to high mortality of older adults and elderly. Immediate
availability for targeted experimental and clinical interrogations of potential
COVID-19 pandemic mitigation agents, namely Vitamin D and Quercetin, as well as
of the highly selective (K<sub>i, </sub>600 pm) intrinsically-specific FURIN
inhibitor (a1-antitrypsin Portland (a1-PDX), is considered an encouraging
factor. 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. </p><p>
<b></b><i></i><u></u><sub></sub><sup></sup><br></p>
First Edition of Hahnemann's Organon: Celebrating its 200th Anniversary
