About: Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells

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About: Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells
Creator	Glinsky, Gennadi
Source	Medline; PMC
abstract	Genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomic-guided molecular maps of upstream regulatory elements, their expression and functions in the human body, and 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; RUNX1; HNF4a; JNK1/c-FOS) were then employed to identify existing drugs manifesting in their effects on gene expression signatures of potential coronavirus infection mitigation agents. Using this strategy, vitamin D and quercetin have been identified as putative 2019 coronavirus disease (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 structurally similar quercetin, luteolin, and eriodictyol could serve as scaffolds for the development of efficient inhibitors of SARS-CoV-2 infection. In agreement with this notion, quercetin alters the 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 the coronavirus pandemic. Estradiol, in contrast with testosterone, affects the expression of the 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 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 the high mortality of older adults and the 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 (Ki, 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. 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 the results of present analyses, a randomized interventional clinical trial evaluating effects of estradiol on severity of the coronavirus infection in COVID19+ and presumptive COVID19+ patients and two interventional randomized clinical trials evaluating effects of vitamin D on prevention and treatment of COVID-19 were listed on the ClinicalTrials.gov website.
has issue date	2020-05-21(xsd:dateTime)
bibo:doi	10.3390/biomedicines8050129
bibo:pmid	32455629
has license	cc-by
sha1sum (hex)	a652b715bf1d0fbe2c4a33718fe570a1b1759c9e
schema:url	https://doi.org/10.3390/biomedicines8050129
resource representing a document's title	Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells
has PubMed Central identifier	PMC7277789
has PubMed identifier	32455629
schema:publication	Biomedicines
resource representing a document's body	covid:a652b715bf1d0fbe2c4a33718fe570a1b1759c9e#body_text
is schema:about of	named entity 'viral proteins' named entity 'observational studies' named entity 'luteolin' named entity 'vitamin' named entity 'virus' named entity 'protein targets' named entity 'SARS-CoV-2' named entity 'repressors' named entity 'testosterone' named entity 'coronavirus infection' named entity 'gene expression' named entity 'Infection' named entity 'viral proteins' named entity 'quercetin' named entity 'INSIG1' named entity 'estradiol' named entity 'vitamin' named entity 'clinical trial' named entity 'SARS-CoV-2' named entity 'ACE2' named entity 'SARS-CoV-2' named entity 'gene expression' named entity 'estradiol' named entity 'coronavirus infection' named entity 'SARS-CoV-2' named entity 'quercetin' named entity 'SARS-CoV-2' named entity 'FURIN' named entity 'human genes' named entity 'immune cells' named entity 'SARS-CoV-2' named entity 'coronavirus infection' named entity 'Quercetin' named entity 'SARS-CoV-2' named entity 'COVID-19 Pandemic' named entity 'quercetin' named entity 'United States' named entity 'quercetin' named entity 'FURIN' named entity 'vitamin' named entity 'serum' named entity 'pathophysiologically' named entity 'interactome' named entity 'infection' named entity 'quercetin' named entity 'murine' named entity 'vitamin' named entity 'Runx1' named entity 'Natural Killer Cells' named entity 'ACE2' named entity 'genomic regulatory' named entity 'ACE2 receptor' named entity 'ACE2' named entity 'protein targets' named entity 'protein' named entity 'immune cells' named entity 'ACE2 receptor' named entity 'quercetin' named entity 'SARS-CoV-2' named entity 'doxorubicin' named entity 'HIF1a' named entity 'data visualization' named entity 'androgen' named entity 'ACE2' named entity 'testosterone' named entity 'coronavirus infection' named entity 'mortality rates' named entity 'COVID-19 pandemic' named entity 'ACE2' named entity 'COVID' named entity 'quercetin' named entity 'eriodictyol' named entity 'quercetin' named entity 'sialic acid' named entity 'high-affinity' named entity 'Gene Ontology' named entity 'serum' named entity 'vitamin D3' named entity 'repressors' named entity 'FURIN' named entity 'gene expression'

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