Tripartite combination of potential pandemic mitigation agents: Vitamin D, Quercetin, and Estradiol manifest properties of candidate medicinal agents for mitigation of the severity of pandemic COVID-19 defined by genomics-guided tracing of SARS-CoV-2 targets in human cells

Genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN , 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 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 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 Similarly, Vitamin D may interfere with functions of 19 of 27 (70%) of the SARS-CoV-2 proteins by altering expression of 84 of 332 (25%) of human genes encoding protein targets of SARS-CoV-2 Considering the potential effects of both Quercetin and Vitamin D, the inference could be made that functions of 25 of 27 (93%) of SARS-CoV-2 proteins in human cells may be altered GSEA and EPEs 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 SARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during coronavirus pandemic Estradiol, in contrast with Testosterone, affects expression of a majority of human genes (203 of 332;61%) encoding SARS-CoV-2 targets, thus potentially interfering with functions of 26 of 27 SARS-CoV-2 viral proteins A hypothetical tripartite combination consisting of Quercetin/Vitamin D/Estradiol may affect expression of 244 of 332 (73%) human genes encoding SARS-CoV-2 targets 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 sui, /su600 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-utargeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically-viable interventions to combat the COVID-19 pandemic Specifically, gene expression profiles of Vitamin D and Quercetin activities and their established safety records as over-the-counter medicinal substances strongly argue that they may represent viable candidates for further considerations of their potential utility as COVID-19 pandemic mitigation agents In line with results of present analyses, a randomized intervent onal clinical trial entitled â€œPhase