Linkage of theleuS, emtB, andchr genes on chromosome 5 in humans and expression of human genes encoding protein synthetic components in human-Chinese hamster hybrids

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 (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 results of present analyses, a randomized interventional clinical trial entitled “Phase II Clinical Trial of Estradiol to Reduce Severity of COVID19 Infection in COVID19+ and Presumptive COVID19+ Patients” has been posted on ClinicalTrials.gov website (<a href="https://clinicaltrials.gov/ct2/show/NCT04359329">https://clinicaltrials.gov/ct2/show/NCT04359329</a> ) and two interventional randomized clinical trials evaluating effects of Vitamin D on prevention and treatment of COVID-19 were listed on ClinicalTrials.gov website (<a href="https://www.clinicaltrials.gov/ct2/show/NCT04334005">https://www.clinicaltrials.gov/ct2/show/NCT04334005</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT04344041">https://clinicaltrials.gov/ct2/show/NCT04344041</a> ).

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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.

10.26434/chemrxiv.12052512 ◽

2020 ◽

Author(s):

Gennadi Glinsky

Keyword(s):

Vitamin D ◽

Immune Cells ◽

Randomized Clinical Trials ◽

Viral Proteins ◽

Human Cells ◽

Protein Targets ◽

Human Genes ◽

Genes Encoding ◽

Coronavirus Infection ◽

Encoding Protein

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 (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 results of present analyses, a randomized interventional clinical trial entitled “Phase II Clinical Trial of Estradiol to Reduce Severity of COVID19 Infection in COVID19+ and Presumptive COVID19+ Patients” has been posted on ClinicalTrials.gov website (<a href="https://clinicaltrials.gov/ct2/show/NCT04359329">https://clinicaltrials.gov/ct2/show/NCT04359329</a> ) and two interventional randomized clinical trials evaluating effects of Vitamin D on prevention and treatment of COVID-19 were listed on ClinicalTrials.gov website (<a href="https://www.clinicaltrials.gov/ct2/show/NCT04334005">https://www.clinicaltrials.gov/ct2/show/NCT04334005</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT04344041">https://clinicaltrials.gov/ct2/show/NCT04344041</a> ).

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Structure and evolution of the human genes encoding protein C and coagulation factor IX

Journal of Cellular Biochemistry ◽

10.1002/jcb.240330305 ◽

1987 ◽

Vol 33 (3) ◽

pp. 185-190 ◽

Cited By ~ 5

Author(s):

George L. Long

Keyword(s):

Protein C ◽

Coagulation Factor ◽

Factor Ix ◽

Coagulation Factor Ix ◽

Human Genes ◽

Genes Encoding ◽

Encoding Protein

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Efficient procedure for transferring specific human genes into Chinese hamster cell mutants: interspecific transfer of the human genes encoding leucyl- and asparaginyl-tRNA synthetases.

Molecular and Cellular Biology ◽

10.1128/mcb.3.5.892 ◽

1983 ◽

Vol 3 (5) ◽

pp. 892-902 ◽

Cited By ~ 28

Author(s):

R E Cirullo ◽

S Dana ◽

J J Wasmuth

Keyword(s):

Human Genome ◽

Cell Lines ◽

Chinese Hamster ◽

Chinese Hamster Cell ◽

Trna Synthetase ◽

Temperature Sensitive ◽

Efficient Procedure ◽

Human Dna ◽

Human Genes ◽

Genes Encoding

We have developed a simple and efficient procedure for transferring specific human genes into mutant Chinese hamster ovary cell recipients that does not rely on using calcium phosphate-precipitated high-molecular-weight DNA. Interspecific cell hybrids between human leukocytes and temperature-sensitive Chinese hamster cell mutants with either a thermolabile leucyl-tRNA synthetase or a thermolabile asparaginyl-tRNA synthetase were used as the starting material in these experiments. These hybrids contain only one or a few human chromosomes and require expression of the appropriate human aminoacyl-tRNA synthetase gene to grow at 39 degrees C. Hybrids were exposed to very high doses of gamma-irradiation to extensively fragment the chromosomes and re-fused immediately to the original temperature-sensitive Chinese hamster mutant, and secondary hybrids were isolated at 39 degrees C. Secondary hybrids, which had retained small fragments of the human genome containing the selected gene, were subjected to another round of irradiation, refusion, and selection at 39 degrees C to reduce the amount of human DNA even further. Using this procedure, we have constructed Chinese hamster cell lines that express the human genes encoding either asparaginyl- or leucyl-tRNA synthetase, yet less than 0.1% of their DNA is derived from the human genome, as quantitated by a sensitive dot-blot nucleic acid hybridization procedure. Analysis of these cell lines with Southern blots confirmed the presence of a small number of restriction endonuclease fragments containing human DNA specifically. These cell lines represent a convenient and simple means to clone the human genomic sequences of interest.

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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.

10.26434/chemrxiv.12052512.v10 ◽

2020 ◽

Author(s):

Gennadi Glinsky

Keyword(s):

Vitamin D ◽

Immune Cells ◽

Randomized Clinical Trials ◽

Viral Proteins ◽

Human Cells ◽

Protein Targets ◽

Human Genes ◽

Genes Encoding ◽

Coronavirus Infection ◽

Encoding Protein

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 (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 results of present analyses, a randomized interventional clinical trial entitled “Phase II Clinical Trial of Estradiol to Reduce Severity of COVID19 Infection in COVID19+ and Presumptive COVID19+ Patients” has been posted on ClinicalTrials.gov website (<a href="https://clinicaltrials.gov/ct2/show/NCT04359329">https://clinicaltrials.gov/ct2/show/NCT04359329</a> ) and two interventional randomized clinical trials evaluating effects of Vitamin D on prevention and treatment of COVID-19 were listed on ClinicalTrials.gov website (<a href="https://www.clinicaltrials.gov/ct2/show/NCT04334005">https://www.clinicaltrials.gov/ct2/show/NCT04334005</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT04344041">https://clinicaltrials.gov/ct2/show/NCT04344041</a> ).

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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.

10.26434/chemrxiv.12052512.v8 ◽

2020 ◽

Author(s):

Gennadi Glinsky

Keyword(s):

Vitamin D ◽

Immune Cells ◽

Randomized Clinical Trials ◽

Viral Proteins ◽

Human Cells ◽

Protein Targets ◽

Human Genes ◽

Genes Encoding ◽

Coronavirus Infection ◽

Encoding Protein

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 (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 results of present analyses, a randomized interventional clinical trial entitled “Phase II Clinical Trial of Estradiol to Reduce Severity of COVID19 Infection in COVID19+ and Presumptive COVID19+ Patients” has been posted on ClinicalTrials.gov website (<a href="https://clinicaltrials.gov/ct2/show/NCT04359329">https://clinicaltrials.gov/ct2/show/NCT04359329</a> ) and two interventional randomized clinical trials evaluating effects of Vitamin D on prevention and treatment of COVID-19 were listed on ClinicalTrials.gov website (<a href="https://www.clinicaltrials.gov/ct2/show/NCT04334005">https://www.clinicaltrials.gov/ct2/show/NCT04334005</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT04344041">https://clinicaltrials.gov/ct2/show/NCT04344041</a> ).

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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.

10.26434/chemrxiv.12052512.v7 ◽

2020 ◽

Cited By ~ 1

Author(s):

Gennadi Glinsky

Keyword(s):

Clinical Trial ◽

Vitamin D ◽

Viral Proteins ◽

Human Cells ◽

Protein Targets ◽

Human Genes ◽

Genes Encoding ◽

Completion Date ◽

Coronavirus Infection ◽

Encoding Protein

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, 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. 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. In agreement with present analyses, a randomized interventional clinical trial entitled “Phase II Clinical Trial of Estradiol to Reduce Severity of COVID19 Infection in COVID19+ and Presumptive COVID19+ Patients” has been posted on ClinicalTrials.gov with the start date April 20 and completion date November 20, 2020 (<a href="https://clinicaltrials.gov/ct2/show/NCT04359329">https://clinicaltrials.gov/ct2/show/NCT04359329</a> ). 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 (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. Significantly, the interventional randomized clinical trial entitled “Effect of Vitamin D Administration on Prevention and Treatment of Mild Forms of Suspected COVID-19” was listed on ClinicalTrials.gov website (<a href="https://www.clinicaltrials.gov/ct2/show/NCT04334005">https://www.clinicaltrials.gov/ct2/show/NCT04334005</a> ) with the starting date April 10 and completion date June 30, 2020.

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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.

10.26434/chemrxiv.12052512.v11 ◽

2020 ◽

Author(s):

Gennadi Glinsky

Keyword(s):

Vitamin D ◽

Immune Cells ◽

Randomized Clinical Trials ◽

Viral Proteins ◽

Human Cells ◽

Protein Targets ◽

Human Genes ◽

Genes Encoding ◽

Coronavirus Infection ◽

Encoding Protein

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 (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 results of present analyses, a randomized interventional clinical trial entitled “Phase II Clinical Trial of Estradiol to Reduce Severity of COVID19 Infection in COVID19+ and Presumptive COVID19+ Patients” has been posted on ClinicalTrials.gov website (<a href="https://clinicaltrials.gov/ct2/show/NCT04359329">https://clinicaltrials.gov/ct2/show/NCT04359329</a> ) and two interventional randomized clinical trials evaluating effects of Vitamin D on prevention and treatment of COVID-19 were listed on ClinicalTrials.gov website (<a href="https://www.clinicaltrials.gov/ct2/show/NCT04334005">https://www.clinicaltrials.gov/ct2/show/NCT04334005</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT04344041">https://clinicaltrials.gov/ct2/show/NCT04344041</a> ).

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Vitamin D and Quercetin 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.

10.26434/chemrxiv.12052512.v6 ◽

2020 ◽

Author(s):

Gennadi Glinsky

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Human Body ◽

Immune Cells ◽

Human Cells ◽

Protein Targets ◽

Human Genes ◽

Genes Encoding ◽

Coronavirus Infection ◽

Encoding Protein

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. 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. 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, 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 (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. Significantly, the interventional randomized clinical trial entitled “Effect of Vitamin D Administration on Prevention and Treatment of Mild Forms of Suspected COVID-19” was listed on ClinicalTrials.gov website (<a href="https://www.clinicaltrials.gov/ct2/show/NCT04334005">https://www.clinicaltrials.gov/ct2/show/NCT04334005</a> ) with the starting date April 10 and completion date June 30, 2020.

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