The document discusses how COVID-19 may attack hemoglobin and disrupt human heme metabolism. It finds that the ORF8 and spike proteins can bind to porphyrin, while orf1ab, ORF10, and ORF3a can coordinate to attack the heme on hemoglobin's beta chain. This releases iron to form porphyrin, reducing oxygen carrying capacity and causing lung inflammation. It also interferes with human heme pathways. Chloroquine and favipiravir are found to inhibit these actions and relieve symptoms by molecular docking analysis.
1) A study found that hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), was effective at inhibiting SARS-CoV-2 infection in vitro and may be a potential treatment for COVID-19.
2) Experiments showed that HCQ was less toxic than CQ but also less potent against SARS-CoV-2 at certain infection levels. However, HCQ's safety profile makes it more suitable than CQ for large-scale use in treating COVID-19 patients.
3) The study suggests that HCQ works by blocking the transport of SARS-CoV-2 from early endosomes to endolysosomes, preventing the virus from releasing its genome. HCQ treatment also
This document summarizes research examining how the HIV envelope protein gp120 induces apoptosis in lung microvascular endothelial cells. The key findings are:
1) Gp120 upregulates surface expression of the proinflammatory cytokine EMAP II and its receptor CXCR3 on endothelial cells in a rapid and robust manner.
2) This upregulation occurs via gp120 signaling through its CXCR4 receptor and activation of the p38 MAPK pathway.
3) Both EMAP II and CXCR3 are essential for gp120-induced endothelial cell apoptosis.
4) The findings suggest a novel mechanism by which HIV infection causes endothelial cell loss and damage, contributing to lung diseases like emphysema.
This document provides information about COVID-19 (coronavirus disease). It discusses the symptoms, transmission, diagnosis and treatment of the disease. The diagnosis sections describe molecular diagnosis using RT-PCR testing of genes like ORF1ab and N, as well as antibody testing methods like ELISA and rapid lateral flow tests. Inflammatory markers associated with COVID-19 are also summarized, including increased levels of cytokines, C-reactive protein, erythrocyte sedimentation rate and liver enzymes. Potential treatments mentioned include antiviral drugs, corticosteroids, remdesivir and chloroquine.
This document discusses hypoxia-inducible factor 1 (HIF-1) and its role in cancer therapy. HIF-1 is a heterodimeric protein composed of HIF-1α and HIF-1β subunits. Under normal oxygen conditions, HIF-1α is hydroxylated and degraded by the von Hippel-Lindau tumor suppressor protein (VHL). Under hypoxic conditions, HIF-1α evades degradation, dimerizes with HIF-1β, and activates genes involved in oxygen homeostasis, angiogenesis, glucose metabolism, and cell proliferation. Targeting HIF-1α stabilization and activity is a potential strategy for cancer therapy. The document reviews the
HCV was discovered in 1989 as a major cause of non-A, non-B hepatitis. It is a single stranded RNA virus of the Flaviviridae family. An estimated 130-170 million people worldwide are chronically infected, making it a significant global health burden.
HCV has an enveloped virion that is 50-80 nm in diameter with E1 and E2 glycoprotein spikes. Its positive-sense single stranded RNA genome is translated into a polyprotein that is cleaved into structural and non-structural proteins. The non-structural proteins NS3, NS4, NS5B are involved in replication and assembly of new virions.
Older treatments for HCV involved peg
Biochemical biomarkers alterations in coronavirus disease 2019sp medical coolege
The document discusses biochemical biomarker alterations in patients with COVID-19. It describes three stages of the disease - early infection, pulmonary phase, and hyperinflammation phase - each characterized by specific biochemical changes. Lymphopenia, elevated inflammatory markers, coagulation abnormalities, and evidence of multi-organ damage are common in severe COVID-19 patients. The SARS-CoV-2 virus can directly infect cells through the ACE2 receptor, found in many organs, contributing to systemic complications. Laboratory testing plays an important role in disease management and outcome prediction by identifying changes in blood cells, inflammation, organ function, and other markers.
Serum cytokine TNF-alpha and hemoglobin levels in Plasmodium falciparum malar...Apollo Hospitals
This document summarizes a study that assessed the correlation between levels of the cytokine TNF-alpha and hemoglobin in patients infected with Plasmodium falciparum (Pf malaria) compared to healthy controls. The study found significantly higher levels of TNF-alpha and lower hemoglobin levels in Pf malaria patients compared to controls. A strong negative correlation was observed between TNF-alpha and hemoglobin levels in Pf malaria patients, indicating that higher TNF-alpha is associated with more severe anemia. The results suggest TNF-alpha may play an important role in the pathogenesis of anemia caused by Pf malaria.
This case report describes a 58-year-old female diagnosed with pulmonary alveolar proteinosis (PAP) who showed recurrence after 5 whole lung lavages. She responded well to subcutaneous injections of granulocyte macrophage colony-stimulating factor (GM-CSF) therapy, indicating it is a promising alternative for those requiring repeated lavages. Whole lung lavage is currently the primary treatment for PAP but does not correct the underlying defect. In contrast, GM-CSF therapy aims to supplement deficient GM-CSF signaling and has shown clinical improvement in PAP patients in multiple studies. This patient demonstrated marked radiological and clinical improvement after 1 year on GM-CSF therapy.
1) A study found that hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), was effective at inhibiting SARS-CoV-2 infection in vitro and may be a potential treatment for COVID-19.
2) Experiments showed that HCQ was less toxic than CQ but also less potent against SARS-CoV-2 at certain infection levels. However, HCQ's safety profile makes it more suitable than CQ for large-scale use in treating COVID-19 patients.
3) The study suggests that HCQ works by blocking the transport of SARS-CoV-2 from early endosomes to endolysosomes, preventing the virus from releasing its genome. HCQ treatment also
This document summarizes research examining how the HIV envelope protein gp120 induces apoptosis in lung microvascular endothelial cells. The key findings are:
1) Gp120 upregulates surface expression of the proinflammatory cytokine EMAP II and its receptor CXCR3 on endothelial cells in a rapid and robust manner.
2) This upregulation occurs via gp120 signaling through its CXCR4 receptor and activation of the p38 MAPK pathway.
3) Both EMAP II and CXCR3 are essential for gp120-induced endothelial cell apoptosis.
4) The findings suggest a novel mechanism by which HIV infection causes endothelial cell loss and damage, contributing to lung diseases like emphysema.
This document provides information about COVID-19 (coronavirus disease). It discusses the symptoms, transmission, diagnosis and treatment of the disease. The diagnosis sections describe molecular diagnosis using RT-PCR testing of genes like ORF1ab and N, as well as antibody testing methods like ELISA and rapid lateral flow tests. Inflammatory markers associated with COVID-19 are also summarized, including increased levels of cytokines, C-reactive protein, erythrocyte sedimentation rate and liver enzymes. Potential treatments mentioned include antiviral drugs, corticosteroids, remdesivir and chloroquine.
This document discusses hypoxia-inducible factor 1 (HIF-1) and its role in cancer therapy. HIF-1 is a heterodimeric protein composed of HIF-1α and HIF-1β subunits. Under normal oxygen conditions, HIF-1α is hydroxylated and degraded by the von Hippel-Lindau tumor suppressor protein (VHL). Under hypoxic conditions, HIF-1α evades degradation, dimerizes with HIF-1β, and activates genes involved in oxygen homeostasis, angiogenesis, glucose metabolism, and cell proliferation. Targeting HIF-1α stabilization and activity is a potential strategy for cancer therapy. The document reviews the
HCV was discovered in 1989 as a major cause of non-A, non-B hepatitis. It is a single stranded RNA virus of the Flaviviridae family. An estimated 130-170 million people worldwide are chronically infected, making it a significant global health burden.
HCV has an enveloped virion that is 50-80 nm in diameter with E1 and E2 glycoprotein spikes. Its positive-sense single stranded RNA genome is translated into a polyprotein that is cleaved into structural and non-structural proteins. The non-structural proteins NS3, NS4, NS5B are involved in replication and assembly of new virions.
Older treatments for HCV involved peg
Biochemical biomarkers alterations in coronavirus disease 2019sp medical coolege
The document discusses biochemical biomarker alterations in patients with COVID-19. It describes three stages of the disease - early infection, pulmonary phase, and hyperinflammation phase - each characterized by specific biochemical changes. Lymphopenia, elevated inflammatory markers, coagulation abnormalities, and evidence of multi-organ damage are common in severe COVID-19 patients. The SARS-CoV-2 virus can directly infect cells through the ACE2 receptor, found in many organs, contributing to systemic complications. Laboratory testing plays an important role in disease management and outcome prediction by identifying changes in blood cells, inflammation, organ function, and other markers.
Serum cytokine TNF-alpha and hemoglobin levels in Plasmodium falciparum malar...Apollo Hospitals
This document summarizes a study that assessed the correlation between levels of the cytokine TNF-alpha and hemoglobin in patients infected with Plasmodium falciparum (Pf malaria) compared to healthy controls. The study found significantly higher levels of TNF-alpha and lower hemoglobin levels in Pf malaria patients compared to controls. A strong negative correlation was observed between TNF-alpha and hemoglobin levels in Pf malaria patients, indicating that higher TNF-alpha is associated with more severe anemia. The results suggest TNF-alpha may play an important role in the pathogenesis of anemia caused by Pf malaria.
This case report describes a 58-year-old female diagnosed with pulmonary alveolar proteinosis (PAP) who showed recurrence after 5 whole lung lavages. She responded well to subcutaneous injections of granulocyte macrophage colony-stimulating factor (GM-CSF) therapy, indicating it is a promising alternative for those requiring repeated lavages. Whole lung lavage is currently the primary treatment for PAP but does not correct the underlying defect. In contrast, GM-CSF therapy aims to supplement deficient GM-CSF signaling and has shown clinical improvement in PAP patients in multiple studies. This patient demonstrated marked radiological and clinical improvement after 1 year on GM-CSF therapy.
COVID-19: Attacks to Haemoglobin and Captures the Porphyrin to Inhibit Human ...GuttiPavan
1) The document discusses how COVID-19 may attack hemoglobin and disrupt human heme metabolism. It is proposed that viral proteins can attack hemoglobin, causing it to dissociate into iron and porphyrins.
2) Certain viral proteins (ORF8 and surface glycoproteins) are then able to capture the released porphyrins. Other viral proteins (orf1ab, ORF10, ORF3a) can attack the heme on hemoglobin subunits.
3) This disruption of hemoglobin and heme metabolism limits oxygen exchange in the lungs, exacerbating respiratory symptoms. Chloroquine may inhibit these attacks on heme and prevent porphyrin binding, relieving symptoms
Enhancing Solubilization of Hydrophobic ORF3 Product of HEV in Bacterial Expr...Allyson Luo
This study aimed to enhance the expression and solubility of the vp13 protein from hepatitis E virus (HEV) by expressing it as a fusion protein with maltose binding protein (MBP) in E. coli. The researchers cloned the ORF3 gene encoding vp13 into a bacterial expression vector with an MBP tag. Initial expression trials found most of the MBP-vp13 fusion protein was insoluble. The researchers then optimized induction conditions, finding induction at 18°C and addition of 1% glucose led to efficient expression of soluble MBP-vp13 fusion protein. This enhanced solubilization and purification of vp13, which will facilitate further study of its structure and function.
Fenótipos e biomarcadores na exacerbação da DPOCFlávia Salame
This study investigated biomarkers in acute exacerbations of chronic obstructive pulmonary disease (COPD) to identify distinct biologic clusters and biomarkers that recognize clinical phenotypes. The study observed 145 COPD patients over 1 year, capturing 182 exacerbations. Four biologic exacerbation clusters were identified: bacterial-, viral-, eosinophilic-predominant, and a "pauciinflammatory" cluster with limited inflammatory changes. 55% of exacerbations were associated with bacteria, 29% with virus, and 28% with sputum eosinophilia. Sputum IL-1β, serum CXCL10, and peripheral eosinophil levels best identified the bacterial, viral, and eosinophilic phenotypes respectively. The study deline
Fenótipos e biomarcadores de exacerbação da DPOCFlávia Salame
This study identified four distinct biologic clusters associated with acute exacerbations of chronic obstructive pulmonary disease (COPD) using cluster analysis of biomarkers:
1) A bacterial-predominant cluster
2) A viral-predominant cluster
3) An eosinophilic-predominant cluster
4) A fourth cluster with limited changes in inflammation termed "pauciinflammatory".
Certain biomarkers were found to best identify the clinical phenotypes associated with these clusters: sputum IL-1β for bacterial exacerbations, serum CXCL10 for viral exacerbations, and peripheral eosinophil percentage for eosinophilic exacerbations. These biomarkers may help direct phenotype-specific treatment of COPD exacerbations
Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug has interesting biochemical properties that might be applied against some viral infections. Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses. Its best-studied effects are those against HIV replication, which are being tested in clinical trials. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor alpha and interleukin 6, which mediate the inflammatory complications of several viral diseases. We review the available information on the effects of chloroquine on viral infections, raising the question of whether this old drug may experience a revival in the clinical management of viral diseases such as AIDS and severe acute respiratory syndrome, which afflict mankind in the era of globalisation.
Chlorogenic acid may be a potent inhibitor of dimeric SARS-CoV-2 main proteas...LucyPi1
Abstract Background: Since the emergence of coronavirus disease 2019 to date, there is no available approved drug or definitive treatment for coronavirus disease 2019 viral infection, and the identification of novel hits against therapeutic targets has become a global emergency. Echinacea purpurea is a traditional herb utilized to treat cough, fever, sore throat, respiratory tract infection, and so on as an immune stimulant. In this study, in silico molecular docking approach was used to screen phytocompounds from E. purpurea against severe acute respiratory syndrome coronavirus 2 main protease 3C-like protease (3CLpro) and severe acute respiratory syndrome coronavirus main peptidase (96% sequence similarity) to blunt the viral gene expression and viral replication. Methods: Initially, we screened phytocompounds for their druggability and ADMET property. Furthermore, x-ray crystallographic structures of main proteases 3CLpro and main peptidase having Protein Data Bank ID 6LU7 and 2GTB were used as protein targets for the identification of potential drug candidates. We performed docking using AutoDock Vina by PyRx 0.8 software. BIOVIA Discovery Studio Visualizer v2019 was used to analyze ligand-protein complex. The probable protein targets of the selected compound were predicted by BindingDB (P ≥ 0.7). STRING and Kyoto Encyclopedia of Genes and Genomes pathways are utilized to identify the molecular pathways modulated by the predicted targets (FDR ≤ 0.05), and the network interaction between compounds and protein pathways was constricted by Cytoscape 3.6.1. Results: Among all the compounds, chlorogenic acid showed druggable characteristics and scored the lowest binding energy with main protease and main peptidase via interacting with active site 1 domain amino acid residues. Interestingly, chlorogenic acid interacted with Phe140 main protease 3CLpro, which is potentially involved in the dimerization. Enrichment analysis identified chlorogenic acid to modulate insulin resistance, necroptosis, interleukin-17, tumor necrosis factor signaling pathway, legionellosis, T helper 17 cell differentiation, advanced glycation end products and receptor for advanced glycation end products, mitogen-activated protein kinase, Ras, estrogen, vascular endothelial growth factor, B-cell receptor, nuclear factor kappa B, Rap1, hypoxia inducible factor-1, phosphatidylinositide 3-kinase-Akt, insulin, mechanistic target of rapamycin, p53, retinoic acid inducible gene I like receptor, and ErbB signaling pathways. Conclusion: Chlorogenic acid may act as a potent main protease 3CLpro inhibitor and may also inhibit the severe acute respiratory syndrome coronavirus 2 dimerization, viral gene expression, and replication within the lung epithelium. Chlorogenic acid may go a long way in finding one of the multipronged solutions to tackle coronavirus disease 2019 viral infection in the future.
Insignt from nono medicine into chloroquine efficacy against COVID-19Valentina Corona
Chloroquine, an approved malaria drug, may have potential therapeutic effects against COVID-19 based on preliminary clinical trials and studies. Chloroquine is known to inhibit endocytosis and increase lysosomal pH, which could interfere with SARS-CoV-2 cellular entry and fusion. Specifically, chloroquine may suppress the protein PICALM, reducing clathrin-mediated endocytosis of SARS-CoV-2. However, more clinical trial data is still needed to verify chloroquine's efficacy against COVID-19, and further studies aim to better understand chloroquine's mechanisms of action and optimal dosing protocols.
Covid-19 is caused by the SARS-CoV-2 virus. It was first identified in Wuhan, China in December 2019 and has since spread globally in a pandemic. Symptoms can range from mild to severe and include loss of taste/smell, breathing difficulties, fever and cough. Testing methods include RT-PCR. Coronaviruses are spherical with spikes and a lipid bilayer. They have a large RNA genome and replicate by translating their genome inside host cells and assembling new virus particles which are then released.
Calprotectin (CP) is a metal-chelating protein produced by neutrophils during inflammation. CP inhibits the growth of Helicobacter pylori, a major risk factor for gastric cancer, by sequestering the metals manganese and zinc. Studies show that CP reduces the activity of H. pylori's cag Type IV Secretion System (T4SS) in a zinc-dependent manner by inhibiting T4SS pilus biogenesis. This decreases H. pylori's ability to translocate the oncoprotein CagA into gastric cells and reduce inflammation. While CP limits H. pylori growth and virulence, it also allows the bacteria to persist by modulating the inflammatory response.
The document summarizes an innovative respiratory device called AMS-H-03 that provides oxygen and hydrogen gas to COVID-19 patients. It can effectively treat symptoms and provide life support. Clinical studies have shown almost all patients' symptoms and oxygen levels improved after one week of treatment. The device has received approval for use in China's COVID-19 treatment protocols.
This document discusses the potential relationship between the SARS-CoV-2 spike protein and increased risk of thrombosis (blood clots). It summarizes several studies that found:
1) The spike protein can directly activate platelets and promote blood clotting.
2) TNF, which is increased during viral infections, provides a procoagulant stimulus that may contribute to hypercoagulable states.
3) Some COVID-19 patients have developed rare cerebral venous sinus thrombosis, and the spike protein may interact with integrins to enhance viral entry and induce a procoagulant state.
1) There are various COVID-19 vaccine candidates that target different parts of the SARS-CoV-2 spike protein, including the full-length spike protein and the receptor-binding domain (RBD).
2) Some research suggests the RBD may be a better target than the full-length spike protein due to concerns that the full protein could potentially cause immune pathology.
3) However, vaccines using the full-length spike protein aim to better mimic the natural infection and induce antibodies and T-cell responses against multiple epitopes on the spike protein.
Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus.
Most people who fall sick with COVID-19 will experience mild to moderate symptoms and recover without special treatment.
1) SARS-CoV is a coronavirus that emerged in 2002 causing a global pandemic. Its pathogenesis involves aberrant host innate immune responses and viral antagonism of interferon signaling.
2) Models of SARS-CoV infection like human airway epithelial cultures and mouse-adapted SARS-CoV have provided insights into innate immune pathways important for controlling SARS-CoV disease.
3) SARS-CoV encodes several proteins that antagonize type I interferon induction and signaling to evade the host innate immune response, which is an important factor in SARS pathogenesis.
Capstone assignment on Clostridium Perfringens Associates degree in Medical T...write31
- A 96-year-old female was admitted to the hospital with diarrhea, weakness, and fever. Initial labs showed elevated white blood cells and liver enzymes.
- Follow-up labs the next morning showed severe hemolytic anemia. A peripheral smear found evidence of intravascular hemolysis.
- Blood cultures grew Clostridium perfringens. This bacterium produces toxins that lyse red blood cells, causing rapid deterioration seen in the patient.
- Despite antibiotic treatment, the patient's condition continued to worsen and she died within hours, likely from C. perfringens sepsis and toxic shock.
Capstone assignment on Clostridium Perfringens Associates degree in Medical T...write22
- A 96-year-old female was admitted to the hospital with diarrhea, weakness, and fever. Initial labs showed elevated white blood cells and liver enzymes.
- Follow-up labs the next morning showed severe hemolytic anemia. A peripheral smear found evidence of intravascular hemolysis.
- Blood cultures grew Clostridium perfringens. This bacterium produces toxins that lyse red blood cells, causing rapid deterioration seen in the patient.
- C. perfringens infection was likely from the patient's gastrointestinal symptoms. The bacteria entered her bloodstream and toxins caused fatal hemolysis within hours.
Cloning and cDNA Synthesis of PE & PPE Gene of Mycobacterium Strain H37rv5AI Publications
Pathogenic, slow-growing Mycobacterium tuberculosis and other Mycobacterium tuberculosis complex (MTBC) species include the pe/ppe genes. In the pathogen-host connection, these genes are crucial. Despite the fact that the activities of most PE/PPE family proteins are unknown, mounting evidence shows they play a role in M. tuberculosis infection. The role of PE/PPE proteins, which are thought to be involved in the ESX system's action, is investigated. During complicated host-pathogen processes, we also discuss how PE/ PPE proteins are involved in host-pathogen interactions, immune response regulation, and cell fate determination. Finally, we discuss future PE/PPE protein research priorities as well as how present information might be used to develop more accurate diagnostics and vaccines for worldwide TB control. The pe and ppe genes, which are thought to be critical in TB pathogenesis, are only found in mycobacteria. However, nothing is known about how these genes' expression is regulated. Understanding the regulatory control of genes present only in mycobacteria, such as the pe and ppe gene families, might help researchers figure out why the illness is so effective. A transposon mutagenesis method was employed to better understand pe and ppe control. Rv1403c, a previously unknown transcriptional regulator, was discovered as a consequence of this study.
El Colegio Médico Veterinario del Perú recomienda autorizar la venta de ivermectina de uso veterinario para tratar pacientes humanos con COVID-19, debido a la escasez del medicamento. También pide informar a la población sobre los riesgos de la automedicación y monitorear efectos entre la ivermectina y la hidroxicloroquina. Finalmente, ofrece la experiencia de los veterinarios para ayudar a combatir la pandemia.
Este documento presenta propuestas para enfrentar los efectos del COVID-19 en grupos vulnerables en el Perú. Introduce el contexto de nuevos escenarios sociales que surgirán debido a la pandemia y los cambios en la vida cotidiana. Luego, analiza siete grupos sociales clave que se verán afectados: trabajadores informales, migrantes venezolanos, mujeres, niños y jóvenes, población penitenciaria, pueblos indígenas y adultos mayores, con diagnósticos y recomendaciones de polí
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COVID-19: Attacks to Haemoglobin and Captures the Porphyrin to Inhibit Human ...GuttiPavan
1) The document discusses how COVID-19 may attack hemoglobin and disrupt human heme metabolism. It is proposed that viral proteins can attack hemoglobin, causing it to dissociate into iron and porphyrins.
2) Certain viral proteins (ORF8 and surface glycoproteins) are then able to capture the released porphyrins. Other viral proteins (orf1ab, ORF10, ORF3a) can attack the heme on hemoglobin subunits.
3) This disruption of hemoglobin and heme metabolism limits oxygen exchange in the lungs, exacerbating respiratory symptoms. Chloroquine may inhibit these attacks on heme and prevent porphyrin binding, relieving symptoms
Enhancing Solubilization of Hydrophobic ORF3 Product of HEV in Bacterial Expr...Allyson Luo
This study aimed to enhance the expression and solubility of the vp13 protein from hepatitis E virus (HEV) by expressing it as a fusion protein with maltose binding protein (MBP) in E. coli. The researchers cloned the ORF3 gene encoding vp13 into a bacterial expression vector with an MBP tag. Initial expression trials found most of the MBP-vp13 fusion protein was insoluble. The researchers then optimized induction conditions, finding induction at 18°C and addition of 1% glucose led to efficient expression of soluble MBP-vp13 fusion protein. This enhanced solubilization and purification of vp13, which will facilitate further study of its structure and function.
Fenótipos e biomarcadores na exacerbação da DPOCFlávia Salame
This study investigated biomarkers in acute exacerbations of chronic obstructive pulmonary disease (COPD) to identify distinct biologic clusters and biomarkers that recognize clinical phenotypes. The study observed 145 COPD patients over 1 year, capturing 182 exacerbations. Four biologic exacerbation clusters were identified: bacterial-, viral-, eosinophilic-predominant, and a "pauciinflammatory" cluster with limited inflammatory changes. 55% of exacerbations were associated with bacteria, 29% with virus, and 28% with sputum eosinophilia. Sputum IL-1β, serum CXCL10, and peripheral eosinophil levels best identified the bacterial, viral, and eosinophilic phenotypes respectively. The study deline
Fenótipos e biomarcadores de exacerbação da DPOCFlávia Salame
This study identified four distinct biologic clusters associated with acute exacerbations of chronic obstructive pulmonary disease (COPD) using cluster analysis of biomarkers:
1) A bacterial-predominant cluster
2) A viral-predominant cluster
3) An eosinophilic-predominant cluster
4) A fourth cluster with limited changes in inflammation termed "pauciinflammatory".
Certain biomarkers were found to best identify the clinical phenotypes associated with these clusters: sputum IL-1β for bacterial exacerbations, serum CXCL10 for viral exacerbations, and peripheral eosinophil percentage for eosinophilic exacerbations. These biomarkers may help direct phenotype-specific treatment of COPD exacerbations
Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug has interesting biochemical properties that might be applied against some viral infections. Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses. Its best-studied effects are those against HIV replication, which are being tested in clinical trials. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor alpha and interleukin 6, which mediate the inflammatory complications of several viral diseases. We review the available information on the effects of chloroquine on viral infections, raising the question of whether this old drug may experience a revival in the clinical management of viral diseases such as AIDS and severe acute respiratory syndrome, which afflict mankind in the era of globalisation.
Chlorogenic acid may be a potent inhibitor of dimeric SARS-CoV-2 main proteas...LucyPi1
Abstract Background: Since the emergence of coronavirus disease 2019 to date, there is no available approved drug or definitive treatment for coronavirus disease 2019 viral infection, and the identification of novel hits against therapeutic targets has become a global emergency. Echinacea purpurea is a traditional herb utilized to treat cough, fever, sore throat, respiratory tract infection, and so on as an immune stimulant. In this study, in silico molecular docking approach was used to screen phytocompounds from E. purpurea against severe acute respiratory syndrome coronavirus 2 main protease 3C-like protease (3CLpro) and severe acute respiratory syndrome coronavirus main peptidase (96% sequence similarity) to blunt the viral gene expression and viral replication. Methods: Initially, we screened phytocompounds for their druggability and ADMET property. Furthermore, x-ray crystallographic structures of main proteases 3CLpro and main peptidase having Protein Data Bank ID 6LU7 and 2GTB were used as protein targets for the identification of potential drug candidates. We performed docking using AutoDock Vina by PyRx 0.8 software. BIOVIA Discovery Studio Visualizer v2019 was used to analyze ligand-protein complex. The probable protein targets of the selected compound were predicted by BindingDB (P ≥ 0.7). STRING and Kyoto Encyclopedia of Genes and Genomes pathways are utilized to identify the molecular pathways modulated by the predicted targets (FDR ≤ 0.05), and the network interaction between compounds and protein pathways was constricted by Cytoscape 3.6.1. Results: Among all the compounds, chlorogenic acid showed druggable characteristics and scored the lowest binding energy with main protease and main peptidase via interacting with active site 1 domain amino acid residues. Interestingly, chlorogenic acid interacted with Phe140 main protease 3CLpro, which is potentially involved in the dimerization. Enrichment analysis identified chlorogenic acid to modulate insulin resistance, necroptosis, interleukin-17, tumor necrosis factor signaling pathway, legionellosis, T helper 17 cell differentiation, advanced glycation end products and receptor for advanced glycation end products, mitogen-activated protein kinase, Ras, estrogen, vascular endothelial growth factor, B-cell receptor, nuclear factor kappa B, Rap1, hypoxia inducible factor-1, phosphatidylinositide 3-kinase-Akt, insulin, mechanistic target of rapamycin, p53, retinoic acid inducible gene I like receptor, and ErbB signaling pathways. Conclusion: Chlorogenic acid may act as a potent main protease 3CLpro inhibitor and may also inhibit the severe acute respiratory syndrome coronavirus 2 dimerization, viral gene expression, and replication within the lung epithelium. Chlorogenic acid may go a long way in finding one of the multipronged solutions to tackle coronavirus disease 2019 viral infection in the future.
Insignt from nono medicine into chloroquine efficacy against COVID-19Valentina Corona
Chloroquine, an approved malaria drug, may have potential therapeutic effects against COVID-19 based on preliminary clinical trials and studies. Chloroquine is known to inhibit endocytosis and increase lysosomal pH, which could interfere with SARS-CoV-2 cellular entry and fusion. Specifically, chloroquine may suppress the protein PICALM, reducing clathrin-mediated endocytosis of SARS-CoV-2. However, more clinical trial data is still needed to verify chloroquine's efficacy against COVID-19, and further studies aim to better understand chloroquine's mechanisms of action and optimal dosing protocols.
Covid-19 is caused by the SARS-CoV-2 virus. It was first identified in Wuhan, China in December 2019 and has since spread globally in a pandemic. Symptoms can range from mild to severe and include loss of taste/smell, breathing difficulties, fever and cough. Testing methods include RT-PCR. Coronaviruses are spherical with spikes and a lipid bilayer. They have a large RNA genome and replicate by translating their genome inside host cells and assembling new virus particles which are then released.
Calprotectin (CP) is a metal-chelating protein produced by neutrophils during inflammation. CP inhibits the growth of Helicobacter pylori, a major risk factor for gastric cancer, by sequestering the metals manganese and zinc. Studies show that CP reduces the activity of H. pylori's cag Type IV Secretion System (T4SS) in a zinc-dependent manner by inhibiting T4SS pilus biogenesis. This decreases H. pylori's ability to translocate the oncoprotein CagA into gastric cells and reduce inflammation. While CP limits H. pylori growth and virulence, it also allows the bacteria to persist by modulating the inflammatory response.
The document summarizes an innovative respiratory device called AMS-H-03 that provides oxygen and hydrogen gas to COVID-19 patients. It can effectively treat symptoms and provide life support. Clinical studies have shown almost all patients' symptoms and oxygen levels improved after one week of treatment. The device has received approval for use in China's COVID-19 treatment protocols.
This document discusses the potential relationship between the SARS-CoV-2 spike protein and increased risk of thrombosis (blood clots). It summarizes several studies that found:
1) The spike protein can directly activate platelets and promote blood clotting.
2) TNF, which is increased during viral infections, provides a procoagulant stimulus that may contribute to hypercoagulable states.
3) Some COVID-19 patients have developed rare cerebral venous sinus thrombosis, and the spike protein may interact with integrins to enhance viral entry and induce a procoagulant state.
1) There are various COVID-19 vaccine candidates that target different parts of the SARS-CoV-2 spike protein, including the full-length spike protein and the receptor-binding domain (RBD).
2) Some research suggests the RBD may be a better target than the full-length spike protein due to concerns that the full protein could potentially cause immune pathology.
3) However, vaccines using the full-length spike protein aim to better mimic the natural infection and induce antibodies and T-cell responses against multiple epitopes on the spike protein.
Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus.
Most people who fall sick with COVID-19 will experience mild to moderate symptoms and recover without special treatment.
1) SARS-CoV is a coronavirus that emerged in 2002 causing a global pandemic. Its pathogenesis involves aberrant host innate immune responses and viral antagonism of interferon signaling.
2) Models of SARS-CoV infection like human airway epithelial cultures and mouse-adapted SARS-CoV have provided insights into innate immune pathways important for controlling SARS-CoV disease.
3) SARS-CoV encodes several proteins that antagonize type I interferon induction and signaling to evade the host innate immune response, which is an important factor in SARS pathogenesis.
Capstone assignment on Clostridium Perfringens Associates degree in Medical T...write31
- A 96-year-old female was admitted to the hospital with diarrhea, weakness, and fever. Initial labs showed elevated white blood cells and liver enzymes.
- Follow-up labs the next morning showed severe hemolytic anemia. A peripheral smear found evidence of intravascular hemolysis.
- Blood cultures grew Clostridium perfringens. This bacterium produces toxins that lyse red blood cells, causing rapid deterioration seen in the patient.
- Despite antibiotic treatment, the patient's condition continued to worsen and she died within hours, likely from C. perfringens sepsis and toxic shock.
Capstone assignment on Clostridium Perfringens Associates degree in Medical T...write22
- A 96-year-old female was admitted to the hospital with diarrhea, weakness, and fever. Initial labs showed elevated white blood cells and liver enzymes.
- Follow-up labs the next morning showed severe hemolytic anemia. A peripheral smear found evidence of intravascular hemolysis.
- Blood cultures grew Clostridium perfringens. This bacterium produces toxins that lyse red blood cells, causing rapid deterioration seen in the patient.
- C. perfringens infection was likely from the patient's gastrointestinal symptoms. The bacteria entered her bloodstream and toxins caused fatal hemolysis within hours.
Cloning and cDNA Synthesis of PE & PPE Gene of Mycobacterium Strain H37rv5AI Publications
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Covid19 Hemoglobina - Dr. Freddy Flores Malpartida
1. COVID-19: Attacks the 1-Beta Chain of Hemoglobin and
Captures the Porphyrin to Inhibit Human Heme Metabolism
Wenzhong Liu 1,2,
*, Hualan Li2
1
School of Computer Science and Engineering, Sichuan University of Science & Engineering,
Zigong, 643002, China;
2
School of Life Science and Food Engineering, Yibin University, Yibin,644000, China;
*
Correspondence: liuwz@suse.edu.cn;
Abstract
The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused
by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat
coronavirus. In this study, conserved domain analysis, homology modeling, and molecular docking
were used to compare the biological roles of certain proteins of the novel coronavirus. The results
showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time,
orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of
hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin
that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and
inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually
results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic
pathway of the human body, is expected to result in human disease. According to the validation
analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to
form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a
certain extent, effectively relieve the symptoms of respiratory distress. Since the ability of chloroquine
to inhibit structural proteins is not particularly obvious, the therapeutic effect on different people may
be different. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin,
prevent the virus from entering host cells, and catching free porphyrins. This paper is only for academic
discussion, the correctness needs to be confirmed by other laboratories. Due to the side effects and
allergic reactions of drugs such as chloroquine, please consult a qualified doctor for treatment details,
and do not take the medicine yourself.
Keywords: Novel Coronavirus; Respiratory distress; Ground-glass-Like Lung; E2 glycoprotein;
ORF8; orf1ab; chloroquine; Blood; Diabetic; Fluorescence resonance energy transfer; Ancient virus;
Cytokine Storm
1 Introduction
The novel coronavirus pneumonia (COVID-19) is a contagious acute respiratory infectious
disease. Patients with the coronavirus pneumonia have a fever, and the temperature above 38 degrees
with symptoms such as dry cough, fatigue, dyspnea, difficulty breathing, and frost-glass-like symptoms
in the lungs1-3
. A large amount of mucus can be discovered in the dissected tissue without obvious virus
inclusions. This pneumonia was first discovered in December 2019 in the South China Seafood Market
Hubei Province, China4
. The disease is highly transmitted5,6
. Now the number of infected people has
2. reached tens of thousands around the world, and the infected people are not restricted by race and
borders.
Researchers performed virus isolation tests and nucleic acid sequencing to confirm the disease
was caused by a novel coronavirus7,8
. It is noted that the nucleic acid of the novel coronavirus is a
positive-stranded RNA8
. Its structural proteins include: Spike Protein (S), envelope protein (E),
membrane protein (M), and nucleocapsid phosphoprotein. Transcribed non-structural proteins include:
orf1ab, ORF3a, ORF6, ORF7a, ORF10 and ORF8. The novel coronavirus is highly homologous to the
coronavirus in bats9,10
, and has significant homology with SARS virus11,12
. Researchers have studied
the function of novel coronavirus structural proteins and some non-structural proteins13,14
. But, the
novel coronavirus has potential genomic characteristics, some of which are mainly the cause of human
outbreaks15,16
. For example, CoV EIC (Coronavirus envelope protein ion channel) been implicated in
modulating virion release and CoV – host interaction17
. Spike proteins, ORF8 and ORF3a proteins are
significantly different from other known SARS-like coronaviruses, and they may cause more serious
pathogenicity and transmission differences than SARS-CoV18
. Earlier studies find that the novel
coronavirus enters epithelial cells through the spike protein interacting with the human ACE2 receptor
protein on the surface, causing human infection. However, structural analysis of the spike protein (S)
protein of the novel coronavirus reveals that the S protein only weakly binds to the ACE2 receptor
compared to SARS coronavirus19
. Due to the limitations of existing experimental methods, the specific
functions of virual proteins such as ORF8 and surface glycoprotein are still unclear. The pathogenicity
mechanism of the novel coronavirus remains mysterious20
.
Literature21
disclosed biochemical examination indexes of 99 patients with novel coronavirus
pneumonia, and the report also reflected the abnormal phenomenon of hemoglobin-related biochemical
indexes of patients. This report demonstrates that the hemoglobin and neutrophil counts of most
patients have decreased, and the index values of serum ferritin, erythrocyte sedimentation rate,
C-reactive protein, albumin, and lactate dehydrogenase of many patients increase significantly. This
trace implies that the patient's hemoglobin is decreasing, and the heme is increasing, and the body will
accumulate too many harmful iron ions, which will cause inflammation in the body and increase
C-reactive protein and albumin. Cells react to stress due to inflammation, producing large amounts of
serum ferritin to bind free iron ions to reduce damage. Hemoglobin consists of four subunits, 2-α and
2-β, and each subunit has an iron-bound heme22,23
. Heme is an important component of hemoglobin. It
is a porphyrin containing iron. The structure without iron is called porphyrin. When iron is divalent,
hemoglobin can release carbon dioxide and capture oxygen atoms in alveolar cells, and iron is oxidized
to trivalent. When hemoglobin is made available to other cells in the body through the blood, it can
release oxygen atoms and capture carbon dioxide, and iron is reduced to divalent.
There are no particularly effective drugs and vaccines to control the disease against novel
coronaviruses24
. However, there are several old drugs has found in the latest clinical treatments, which
can inhibit some functions of the virus, for example, cloroquine phosphate has a definite effect on the
novel coronavirus pneumonia25
. chloroquine phosphate is an antimalarial drug that has been utilized
clinically for more than 70 years. Experiments show that erythrocytes infected by malaria can cause a
large amount of chloroquine to accumulate in it. The drug leads to the loss of hemoglobin enzyme, and
parasite death due to insufficient amino acids in the growth and development of the parasite. The
therapeutic effect of chloroquine phosphate on novel coronavirus pneumonia suggests that novel
coronavirus pneumonia might be closely related to abnormal hemoglobin metabolism in humans.
Meanwhile, one detail we can notice is that chloroquine is also a commonly used drug for treating
3. porphyria26,27
.
Therefore, it is believed that combining viral proteins and porphyrins will cause a series of human
pathological reactions, such as a decrease in hemoglobin. Because of the severe epidemic, and the
existing conditions with limited experimental testing methods for the proteins’ functions, it is of great
scientific significance to analyze the proteins’ function of the novel coronavirus by bioinformatics
methods.
In this study, conserved domains prediction, homology modeling and molecular docking
techniques were used to analyze the functions of virus-related proteins. This study found that ORF8
and surface glycoprotein had a function to combine with porphyrin to form a complex, while orf1ab,
ORF10, ORF3a coordinately attack the heme on the 1-beta chain of hemoglobin to dissociate the iron
to form the porphyrin. This mechanism of the virus inhibited the normal metabolic pathway of heme,
and made people show symptoms of the disease. Built on the above research results, we also verified
the role of chloroquine phosphate and Favipiravir by molecular docking technology to assist clinical
treatment.
2 Materials and Methods
2.1 Data set
The protein sequences were downloaded from NCBI: All proteins of Wuhan novel coronavirus;
Heme-binding protein; Heme oxidase; Protein sequences were utilized to analyze conserved domain.
All proteins of Wuhan novel coronavirus were also used to construct three-dimensional structures by
homology modeling.
At the same time, the PDB files were downloaded from the PDB database: Crystal structure of
MERS-CoV nsp10_nsp16 complex--5yn5; HEM; Human Oxy-Hemoglobin 6bb5; DEOXY HUMAN
HEMOGLOBIN 1a3n; 0TX; RP. MERS-CoV nsp10_nsp16 complex--5yn5 was used to homology
modeling. HEM, 0TX and 1RP were used to molecular docking. Two Oxy-Hemoglobin were used to
protein docking
2.2 Flow view of bioinformatics analysis
A series of bioinformatics analysis was performed based on published biological protein
sequences in this study. The steps are illustrated in Figure 1: 1. Conserved Domains of Viral Proteins
are analyzed by MEME28-30
Online Server. Conserved domains were used to predict function
differences of viral proteins and human proteins. 2.The three-dimensional structure of viral proteins
was constructed by homology modeling of Swiss-model31,32
. When the sequence length exceeded
5000nt, the homology modeling tool of Discovery-Studio 2016 was adopted. 3. Using molecular
docking technology (LibDock tool) of Discovery-Studio 201633
, the receptor-ligand docking of viral
proteins with human heme (or porphyrins) was simulated. Depending on the results of bioinformatics
analysis, a life cycle modelof the virus was constructed, and the related molecular of the disease was
proposed.
4. Figure 1. Flow view of Bioinformatics Analysis
The workflow is based on evolutionary principles. Although the biological sequence characteristic
of advanced life forms and viral is different, molecules with similar structures can always achieve
similar biological roles. The homology modeling method uses the principle the similar primary
structure of protein sequences has a similar spatial structure. Molecular docking technology is built on
homology modeling or really three-dimensional molecular.
2.3 Analysis of conserved domain
MEME Suite is an online website that integrates many tools of predicting and annotation motif.
The maximum expectation (EM) algorithm is the basis for MEM's identification of the motif. The
motif is a conserved domain of a small sequence in a protein. Motif-based models could assess the
reliability of phylogenetic analysis. After opening the online tool MEME, the protein sequences of
interest are merged into a text file, and the file format remains fasta. Then select the number of motifs
you want to find, and click the "Go" button. At the end of the analysis, the conserved domains are
displayed after clicking the link.
2.4 Homology modeling
SWISS-MODEL is a fully automatic homology modeling server for protein structure, which can
be accessed through a web server. The first step is to enter the Swiss-model, enter the sequence, and
click "Search Template" to perform a simple template search. After the search is completed, you can
choose a template for modeling. A template search will be performed clicking "Build Model" and a
template model is chosen automatically. As can be seen, several templates were searched, and then
numerous models were built. Just a model is chosen here. The model in PDB format is downloaded and
visualized in VMD. SWISS-MODEL only models protein models with sequence lengths less than
5000nt. You can use Discovery-Studio's homology modeling tool to model where the protein sequence
exceeds 5000nt.
Before using Discovery-Studio to model homology of an unknown protein (such as orf1ab), the
pdb structure file of the template protein, such as MERS-CoVnsp10_nsp16 complex 5yn5, should be
downloaded from the PDB database. Next, the sequence alignment tool of Discovery-Studio is utilized
to align homologous sequences between 5yn5 and orf1ab. Then the spatial structure file of orf1ab was
constructed based on the template protein 5yn5.
2.5 Molecular docking technology
5. Molecular docking is the process of finding the best matching pattern between two or more
molecules through geometric matching and energy matching. The steps for using LibDock molecular
docking with Discovery-Studio are as follows:
1. Preparation of a ligand model. Open a ligand file such as HEM, and click “Prepare Ligands” in
the “Dock Ligands” submenu of the “Receptor-Ligand Interactions” menu to generate a heme ligand
model for docking. First delete FE (iron atom) in HEM, and then click the “Prepare Ligands” button,
then the porphyrin ligand model will be generated. With 0 XT is opened, click “Prepare Ligands” again
to get the chloroquine ligand model.
2. Prepare a protein receptor model. Open the protein's pdb file (generated by homology
modeling), and click “Prepare protein” in the “Dock Ligands” submenu of the “Receptor-Ligand
Interactions” menu to generate a protein receptor model for docking.
3. Set docking parameters to achieve docking. Select the generated protein receptor model. From
the “Define and Edit Binding Site” submenus in the “Receptor-Ligand Interactions” menu, click “From
receptor Cavities”. A red sphere appears on the protein receptor model diagram. After you right-click
the red ball, you can modify the radius of the red ball. Then, in the “Receptor-Ligand Interactions”
menu, select “Dock Ligands (LibDock)” in the “Dock Ligands” submenu. In the pop-up box, select the
ligand as the newly established ligand model-ALL, and select the receptor as the newly established
receptor model-ALL, and the sites sphere as the sphere coordinates just established. Finally click RUN
to start docking.
4. Calculate the binding energy and choose the pose with the largest binding energy. After docking
is complete, many locations of ligand will be displayed. Open the docked view, and click the “Caculate
Binding Energies” button in the “Dock Ligands” submenu of the “Receptor-Ligand Interactions” menu.
In the pop-up box, select the receptor as the default value, select ligand as the docked model -ALL, and
then start to calculate the binding energy. Finally, compare the binding energy and choose the pose with
the largest binding energy. The better the stability of the complex, the greater the binding energy.
5. Export the joint section view. For the docked view, after setting the display style of the binding
area, click the "Show 2D Map" button in the "View Interaction" submenu of the "Receptor-Ligand
Interaction" menu to pop up the view of the binding section. This view can be saved as a picture file.
2.6 Protein docking technology
Discovery-Studio's ZDOCK is another molecular docking tool for studying protein interactions.
We used it to study the attack of hemoglobin by viral non-structural proteins. The following is the
docking of orf1ab and hemoglobin, and other docking methods with virus non-structural proteins are
the same. After opening the PBD files of Human Oxy-Hemoglobin 6bb5 and orf1ab protein, click the
"Dock proteins (ZDOCK)" button of "Dock and Analyze Protein Comlexes" under the
"macromolecules" menu. In the pop-up interface, select Human Oxy-Hemoglobin 6bb5 as the receptor,
orf1a as the ligand, and then click the "Run" button. After the computer finishes computing, click on
the "proteinpose" interface and select the pose and cluster with the highest ZDOCK score. It could
obtain the position of orf1ab on Human Oxy-Hemoglobin 6bb5. Deloxy HUMAN HEMOGLOBIN
1a3n has a similar docking pattern with orf1ab protein.
3 RESULTS
3.1Virus structural proteins binding porphyrin
6. In humans, hemoglobin can be degraded into globin and heme. Heme is composed of a porphyrin
and an iron ion, and the iron ion is in the middle of the porphyrin. Heme is insoluble in water and can
be combined with heme-binding proteins to form a complex and be transported to the liver. The
porphyrin is degraded into bilirubin and excreted from the bile duct, and Iron in the molecule can be
reused by the body. If virus proteins can bind to the porphyrin of the heme, they should have the similar
binding ability to the human heme-binding protein, that is, the virus proteins and heme-binding
proteins should have the similar conserved domains. To examine the binding of virus structure proteins
and porphyrin, the following bioinformatics methods were applied in this paper.
First, MEME's online server was employed to search for conserved domains in each viral
structure protein and human heme-binding protein (ID:NP_057071.2 heme-binding protein 1, ID:
EAW47917.1 heme-binding protein 2). Figure 2 presents that three viral proteins (surface glycoprotein,
envelope protein and nucleocapsid phosphoprotein) and heme-binding proteins have conserved
domains, but membrane glycoprotein do not have any conserved domains. p-value values are small,
there were statistically significant. The domains in three viral proteins are different, suggesting the
structural protein's ability to bind porphyrin may be slightly different. Membrane glycoprotein could
not bind to theporphyrin.
7. Figure 2. Conserved domains between structure proteins and human heme-binding proteins. A.
Conserved domains of surface glycoprotein. B. Conserved domains of envelope protein. C. Conserved
domains of membrane glycoprotein. D. Conserved domains of nucleocapsid phosphoprotein.
Next, the Swiss-model online server modeled the surface glycoproteins to produce a
three-dimensional structure, and two kinds of files based on the Spike and E2 templates were selected.
The 3D-structural file of heme was downloaded from the PDB database.
In the end, Discovery-Studio realized molecular docking of surface glycoproteins and the
porphyrin. The docking of the Spike protein with heme (and porphyrin) failed first. E2 glycoprotein
(Figure 3.A) is derived from templates 1zva.1.A. The docking of E2 glycoprotein and heme was also
fruitless. When the iron ion was removed, the heme became a porphyrin, many kinds of docking were
finalized between the E2 glycoprotein and the porphyrin. Calculating the binding energy, the docking
pose with the highest binding energy (7,530,186,265.80kcal/mol) was accepted. The docking result is
exhibited in Figure 4.A-1, which is the molecular model of E2 glycoprotein binds to the porphyrin.
8. Figure 4.A-2 provides a two-dimensional view of the binding section, where 18 amino acids of the E2
glycoprotein interact with the porphyrin.
Analysis of envelope protein adopted the same methods. The template 5x29.1.A was selected as
the 3D structure template of envelope protein (Figure 3.B). Discovery-Studio found several kinds of
docking of the envelope protein and the porphyrin, where the docking pose with the highest binding
energy (219,317.76kcal/mol) was chosen. Figure 4.B-1 shows the docking result, which is the
molecular model of envelope protein binding to the porphyrin. Figure 4.B-2 is the two-dimensional
view of the binding section, where 18 amino acids of the envelope protein interact with the porphyrin.
Same methods were utilized to analyze the nucleocapsid phosphoprotein. The template of the
nucleocapsid phosphoprotein was 1ssk.1.A (Figure 3.C). Discovery-Studio provides the docking
between the nucleocapsid phosphoprotein and the porphyrin with the highest binding energy
(15,532,506.53kcal/mol). Figure 4.C-1 shows the docking result, which is the molecular model of the
nucleocapsid phosphoprotein bind to the porphyrin. Figure 4.C-2 is the two-dimensional view of the
binding section, where 22amino acids of thenucleocapsid phosphoprotein are bound to the porphyrin.
Membrane protein is derived from templates 1zva.1.A. The docking of membrane protein with heme
(and porphyrin) failed. These results signal the surface glycoprotein, envelope protein and nucleocapsid
phosphoprotein could bind to the porphyrin to form a complex.
It was found the binding energy of envelope protein was the lowest, the binding energy of E2
glycoprotein was the highest, and the binding energy of nucleocapsid phosphoprotein was medium. It
means that binding E2 glycoprotein to the porphyrin is the most stable, the binding of nucleocapsid
phosphoprotein to the porphyrin is unstable, and binding envelope protein to the porphyrin is the most
unstable.
After that, the following analysis was carried out to discover whether structural proteins attacked
the heme and dissociate the iron atom to form porphyrins. Heme has an oxidase called heme oxidase,
which oxidizes heme and dissociates the iron ion. If structural proteins could attack heme and
dissociate iron ions, it should have a similar conserved domain as a heme oxidase. MEME's online
server was manipulated to search for conserved domains of structural proteins and heme oxidase
proteins (NP_002124.1: heme oxygenase 1;BAA04789.1: heme oxygenase-2;AAB22110.2: heme
oxygenase-2). As a result, conserved domains of structural proteins were not found (Figure 5).
Combining the results of the previous analysis, that is, structural proteins could only combine with the
porphyrin. It can be possible to inferthe structural proteins did not attack heme and dissociate the iron
atom to form the porphyrin.
9. Figure 3.3D structure schematics of the novel coronavirus proteins by the homology modeling. A. E2
glycoprotein of the surface glycoprotein. B. Envelope protein. C.nucleocapsid phosphoprotein. D.
orf1ab protein. E. ORF8 protein. F. ORF7a protein
10. Figure 4. Molecular docking results of viral structure proteins and the porphyrin (red structure).
A.Molecular docking results of E2 glycoprotein and the porphyrin. B.Molecular docking results of the
envelope protein and the porphyrin. C.Molecular docking results of the nucleocapsid phosphoprotein
and the porphyrin. 1.Viral structure proteins. 2. View of the binding sections
11. Figure 5. Conserved domains between the structure proteins and human heme oxygenase proteins.
A. Conserved domains of surface glycoprotein. B. Conserved domains of envelope protein. C.
Conserved domains of membrane. D. Conserved domains of nucleocapsid phosphoprotein.
3.2 Virus non-structural proteins bind to the porphyrin
If the non-structure proteins (ID:YP_009724396.1) can bind to the porphyrin of heme, it should
have the similar binding ability to the human heme-binding protein. Then, HEME's online server was
used to search for conserved domains between the non-structure proteins and human heme-binding
proteins. Figure 6 shows that five viral proteins (orf1ab, ORF3a, ORF7a, ORF8 and ORF10) and
heme-binding proteins have conserved functional domains, but ORF6 and heme-binding proteins do
12. not have any conserved functional domains. p-value values are small, there were also statistically
significant. The domains in the five viral proteins are different, suggesting the non-structural protein's
ability to bind porphyrin may be slightly different. ORF6 protein dose not bind to porphyrin.
Figure 6. Conserved domains between non-structural proteins and human heme-binding proteins.
A. Conserved domains of orf1ab. B. Conserved domains of ORF3a. C. Conserved domains of ORF6. D.
13. Conserved domains of ORF7a. E. Conserved domains of ORF8. F. Conserved domains of ORF10.
Homology modeling and molecular docking technology were applied to study the characteristics
of orf1ab protein's ability to bind heme. Because swiss-model cannot model the 3D structure of orf1ab
protein sequence with a sequence length exceeding 5000nt, Discovery-Studio was used to homology
modeling. The crystal structure of MERS-CoV nsp10_nsp16 complex 5yn5 and heme were
downloaded from the PDB database. In this study, the crystal structure of MERS-CoV nsp10_nsp16
complex 5yn5 was set as a template to create a homologous structure of orf1ab protein. The default
homologous structure was selected as the orf1ab protein 3D-structure (Figure 3.D). Then molecular
docking of orf1ab protein and porphyrin was finished by Discovery-Studio. orf1ab protein and heme
could not complete the docking experiment, but by removing iron ions to make heme into a porphyrin,
and the radius of action increased, then several types of docking were completed. By calculating the
binding energy, a docking model with the highest binding energy (561,571.10kcal/mol) was selected.
The docking result is shown in Figure 7.A-1, where is the molecular model of the orf1ab protein
binding to the porphyrin. The binding part of the orf1ab protein acts like a clip. It was this clip that
grasps the porphyrin without the iron ion. Figure 7.A-2 shows a two-dimensional view of the binding
section. It can be seen that 18 amino acids of the orf1ab protein are bound to the porphyrin.
To study the binding properties of ORF8 protein to heme, the same analysis steps as the structural
protein method were used. The structure file was created based on the ORF7 template (Figure 3.E).
Several kinds of docking of the ORF8 protein and the porphyrin, where the docking pose with the
highest binding energy (12,804,859.25kcal/mol) was selected. The docking result (Figure 7.B-1)
represents the molecular model of ORF8 protein binding to the porphyrin. Figure 7.B-2 is the
two-dimensional view of the binding section, where 18 amino acids of the ORF8 are bound to the
porphyrin.
Same methods of ORF8 protein were used to analyze the ORF7a protein. The ORF7a’s template
is 1yo4.1.A (Figure 3.F). The ORF7a protein and the porphyrin had the highest binding energy
(37,123.79 kcal/mol). Figure 7.C-1 shows the molecular model of the ORF7a binds to the porphyrin.
Fifteen amino acids of the ORF7a are bound to the porphyrin (Figure 7.C-2). The binding part of the
ORF7a protein also acts like a clip.
Swiss-model could not provide the template for ORF10. ORF6a and ORF3a are derived from
templates 3h08.1.A and 2m6n.1.A, respectively, but the docking of ORF6a (ORF3a) with heme (and
porphyrin) failed.
14. Figure 7. Molecular docking results of viral non-structural proteins and the porphyrin (red).
A.Molecular docking results of the orf1ab protein and the porphyrin. B.Molecular docking results of
15. the ORF8 protein and the porphyrin. C.Molecular docking results of the ORF7a protein and the
porphyrin. 1.Viral non-structural proteins. 2. View of the binding sections
Finally, the following analysis was performed to find out whether non-structural proteins attacked
the heme and dissociated the iron atom to form porphyrins. Here, the same methods as previous
structural proteins, MEME's online server, were used to analyze the conserved domains of
non-structural proteins and heme oxidase proteins (NP_002124.1: heme oxygenase 1;BAA04789.1:
heme oxygenase-2;AAB22110.2: heme oxygenase-2). As shown in Figure 8, ORF10, orf1ab and
ORF3a have conserved domains. Combining the results of the previous analysis, it is showed,
non-structural proteins: ORF10, orf1ab and ORF3a could attack the heme and dissociate the iron atom
to form the porphyrin. However, the p-Value of orf1ab and ORF3a is great than 0.1%.Therefore ORF10
may be the primary protein to attack heme, orf1ab and ORF3a capture the heme or the porphyrin.
The results marked that orf1ab, ORF7a, and ORF8 could bind to the porphyrin, while ORF10,
ORF3a, and ORF6 could not bind to heme (and porphyrin). ORF10, ORF1ab and ORF3a also have the
ability to attack the heme to form a porphyrin. The binding energies of orf1ab, ORF7a, ORF8 and the
porphyrin were compared respectively. It was found the binding energy of ORF7a was the lowest, the
binding energy of ORF8 was the highest, and the binding energy of orf1ab was medium. This means
that binding ORF8 to the porphyrin is the most stable, the binding of orf1ab to the porphyrin is unstable,
and binding ORF7a to the porphyrin is the most unstable. The sequences of ORF10 and ORF6 are short,
so they should be short signal peptides. Therefore, the mechanism by which non-structural proteins
attack heme might be: ORF10, ORF1ab and ORF3a attacked heme and generatedthe porphyrin; ORF6
and ORF7a sentthe porphyrin to ORF8; and ORF8 and the porphyrin formed a stable complex.
16.
17. Figure 8. Conserved domains between non-structure proteins and human heme oxygenase
proteins. A. Conserved domains of orf1ab. B. Conserved domains of ORF3a. C. Conserved domains of
ORF6. D. Conserved domains of ORF7a. E. Conserved domains of ORF8. F. Conserved domains of
ORF10.
3.3 Viral non-structural protein attacks the heme on the beta chain of the
hemoglobin
Porphyrins in the human body are mostly iron porphyrins, that is, heme. And a lot of heme is not
free, but bind to hemoglobin. There was a massive demand of porphyrins for viruses to survive.
Therefore, the novel coronavirus targeted hemoglobin, attacked heme and hunted porphyrins. The
previous analysis results showed that ORF1ab, ORF3a, and ORF10 have domains similar to heme
oxygenase, but only ORF1ab could bind to porphyrin. To study the attack behavior of orf1ab, ORF3a,
and ORF10 proteins, we used the ZDOCK molecular docking technology to examine these three
proteins. ZDOCK molecular docking technology can analyze protein interactions and find the
approximate positions of these three proteins on hemoglobin.
First, we downloaded heme oxygenase 2 (5UC8) from the PDB and used it as a template, and then
utilized the homology modeling tool of Discovery-Studio to generate the 3D structure of ORF10
(Figure 9). Since hemoglobin has two forms of oxidation and deoxygenation, the following analysis
also performs protein molecular docking in these two cases, taking the posture with the highest
ZDOCK score.
Figure 9. homology modeling of ORF10
For deoxyhemoglobin, orf1ab parked in the middle bottom of the 1-alpha and 2-alpha chain near
the 2-alpha chain (Figure 10.A). ORF3a parked in the middle bottom of the 1-alpha and 2-alpha chain
near the 2-alpha chain (Figure 10.B). ORF10 moored on the middle bottom of the 1-beta and 2-beta
chain near the 1-beta chain (Figure 10.C). The possible mechanism was that orf1ab hit the 2-alpha
chain, causing conformations changes in globin protein. ORF3A forced to the 2-alpha chain to attack
the 1-beta chain and exposed its heme. ORF10 quickly attached to the 1-beta chain and directly
impacted the heme of 1-beta chain. When the iron atom dissociated, the heme changed into porphyrin,
and orf1ab finally captured porphyrin. orf1ab played a vital role throughout the attack.
18. Figure 10. Viral non-structural protein attack hemoglobin. A. orf1ab attacks the deoxyhemoglobin.
B. ORF3a attacks the deoxyhemoglobin. C. ORF10 attacks the deoxyhemoglobin. D. orf1ab attacks the
oxidized hemoglobin. E. ORF10 attacks the oxidized hemoglobin. F. ORF3a attacks the oxidized
hemoglobin.
19. For oxidized hemoglobin, orf1ab parked in the middle bottom of the alpha and beta chain and
closed to the alpha chain (Figure 10.A). ORF10 parked below of the beta chain and neared to the outer
(Figure 10.B). ORF3a parked in the middle bottom of the alpha and beta chain and neared to the beta
chain (Figure 10.C). The possible mechanism was that orf1ab bound to the alpha chain and attacked the
beta chain, causing configurational changes in the alpha and beta chains; ORF3 attacked the beta chain
and exposed heme. ORF10 quickly attached the beta chain and directly impacted the iron atoms on the
heme of the beta chain. The heme was dissociated into porphyrin, and orf1ab finally captured
porphyrin. orf1ab played a vital role throughout the attack.
Attack of oxidized hemoglobin by viral proteins will lead to less and less hemoglobin that can
carry oxygen. The invasion of viral proteins on deoxidized hemoglobin will cause less and less
hemoglobin that can carry carbon dioxide and blood sugar. People with diabetes can have unstable
blood sugar. The patient is aggravated by carbon dioxide poisoning. The lung cells have extremely
intense inflammation due to the inability to exchange carbon dioxide and oxygen frequently, which
eventually results in ground-glass-like lung images. Patients with respiratory distress will be made
worse.
3.4 Validation for the effect of chloroquine phosphate
The chemical components in chloroquine phosphate compete with the porphyrin and bind to the
viral protein, thereby inhibiting the viral protein's attack on heme or binding to the porphyrin. To verify
the effect of chloroquine phosphate on the viral molecular mechanism of action, molecular docking
technology was accepted. The structure file of 0TX (chloroquine) was downloaded from the PDB
database. Then molecular docking technology of Discovery-Studio 2016 was used to test the effects of
viral proteins and chloroquine.
Figure 11.A-1 is a schematic diagram of binding chloroquine to a virus surface glycoprotein.
Figure 11.A-2 is the binding region of virus surface glycoprotein. 13 amino acids engaged in the
binding. The binding energy of chloroquine to the E2 glycoprotein of the virus is 3,325,322,829.64
kcal/mol, which is about half the binding energy of the E2 glycoprotein and the porphyrin. According
to the results of Figure 4.A-2, further analysis showed that some amino acids (for example VAL A:952,
ALA A:956, ALA B:956, ASN A:955 etc.) of the E2 glycoprotein could bind to not only chloroquine
phosphate, but also the porphyrins. In other words, the chloroquine has a one-third chance of inhibiting
viral E2 glycoprotein and reducing patient symptoms.
The binding view of the chloroquine and envelope protein is shown in Figure 11.B-1. The binding
energy of the chloroquine and envelope proteinis7,852.58 kcal/mol, which is only equivalent to 4% of
the binding energy of envelope protein and porphyrin. The binding region is shown in Figure 11.B-2.
Figure 4.B-2 and Figure 11.B-2representedsome amino acids (such as LEV E:28, PHE: D:20, VAL
E:25 ) of the envelope protein is not only bound to the chloroquine phosphate, but also to the
porphyrin.
Figure 11.C-1 is a schematic diagram of binding the chloroquine to the nucleocapsid
phosphoprotein. The binding energy of chloroquine to the nucleocapsid phosphoprotein is 198,815.22
kcal/mol, which is only equivalent to the 1.4% of the binding energy of the nucleocapsid
phosphoprotein and the porphyrin. ALA A:50 etc.of nucleocapsid phosphoprotein are involved in
binding (Figure 12.C-2). Figures 4.C-2 and Figures 11.C-2 declared that amino acids of nucleocapsid
phosphoprotein could bind the porphyrin, but could not bind chloroquine.
20. The docking of membrane protein with chloroquine failed.
Figure 11. Molecular docking results of viral structure proteins and the chloroquine (red).
A.Molecular docking results of the E2 glycoprotein and the porphyrin. B.Molecular docking results of
the envelope protein and the porphyrin. C.Molecular docking results of the nucleocapsid
phosphoprotein and the porphyrin. 1.Viral structure proteins. 2. View of the binding sections
21. A schematic diagram of binding chloroquine to the orf1ab protein is shown in Figure 12.A-1.
Binding section of the orf1ab protein is plotted in Figure 12.A-2. The binding energy of chloroquine
and the orf1ab protein is 4,584,302.64 kcal/mol, which equals 8-fold of the binding energy between the
orf1ab and the porphyrin. According to the results of Figure 7.A-2, it was shown that some amino acids
such as MET 7045, PHE 7043, LYS 6836 of orf1ab protein could be not only bound to chloroquine
phosphate, but also to porphyrin.
A schematic diagram of binding chloroquine to the ORF8 protein is shown in Figure 12.B-1.
Figure 12.B-2 shows the binding section of the ORF8. The binding energy of chloroquine to the ORF8
protein is 4,707,657.39 kcal/mol, which is only equivalent to 37% of the binding energy of the ORF8
protein to the porphyrin. According to the result of Figure 7.B-2, it showed the amino acids like as ILE
A:74, ASP A:75,LYS A:53 of ORF8 could not only bind to chloroquine phosphate, but also to the
porphyrin.
A schematic diagram of binding chloroquine to the ORF7a protein is shown in Figure 12.C-1.
Figure 12.C-2 is the view of the binding section. The binding energy of chloroquine to the ORF7a
protein is 497,154.45 kcal / mol, which equals 13-fold of the binding energy of the ORF7a protein to
the porphyrin. According to the results of Figure 7.C-2, it was shown the amino acids such as GLN
A:94, ARG A:78 and LEU A:96 of ORF7aprotein could be not only bound to chloroquine phosphate,
but also to the porphyrin.
The docking of ORF3a, ORF6 and ORF10 proteins with chloroquine failed.
These results marked the chloroquine could inhibit E2 and ORF8 bind to the porphyrin to form a
complex respectively to a certain extent. Meanwhile, chloroquine could prevent orf1ab, ORF3a and
ORF10 to attack the heme to form the porphyrin.
22. Figure 12. Molecular docking results of viral non-structural proteins and the chloroquine (red
structure). A.Molecular docking results of the orf1ab protein and the chloroquine. B.Molecular docking
results of the ORF8 protein and the chloroquine. C.Molecular docking results of the ORF7a protein and
the chloroquine. 1.Viral non-structural proteins. 2. View of the binding sections.
23. 3.5 Validation for the effect of Favipiravir
Favipiravir is the latest anti-novel coronavirus drug with specific therapeutic effects. In
Favipiravir, the most critical ligand is 1RP, which is 6 - fluoro - 3 - oxo - 4 - (5 - O - phosphono - beta -
D - ribofuranosyl ) - 3, 4 - dihydropyrazine - 2 - carboxamide. Following the same method used to
examine chloroquine, we investigated the efficacy of Favipiravir. As can be seen from Table 1,
Favipiravir cannot be bind to E2 glycoprotein and Nucleocapsid, and its binding energy to Envelope
protein, ORF7a, orf1ab is higher than that to porphyrin. It is useful to note that the binding energy of
Envelope protein and Favipiravir is more than 2700 times the binding energy of porphyrin. The
primary function of Envelope protein is to help the virus enter host cells, which shows that Favipiravir
can effectively prevent the virus from infecting human cells. The binding energy of ORF7a to
Favisiravir is 450 times higher than that of porphyrin, indicating that it can effectively avoid the
non-structural protein of the virus capturing porphyrin. The binding energy of orf1ab and Favisiravir is
1.8 times higher than that of porphyrin, which shows that Faifiravir can prevent virus unstructured
protein from attacking heme on hemoglobin. According to previous studies, the binding energy of
orf1ab and Favisiravir is much smaller than that of chloroquine, so Favisiravir's ability to improve
respiratory distress is lower. In summary, the primary role of Favipiravir is to prevent the virus from
entering host cells and catching free porphyrins.
Table 1. Effect of Favipiravir
Virus potein
Porphyrin
(kcal/mol)
Favipiravir
(kcal/mol)
Has
Identical
residues
Target
Target Rate
(Favipiravir
/Porphyrin)
E2 glycoprotein 7,530,186,265.80 - - - -
Envelope protein 219,317.76 597,814,480.55 Yes Yes 2,725.79
Nucleocapsid 15,532,506.53 - - - -
orf1ab 561,571.10 1,052,489.88 Yes Yes 1.87
ORF8 12,804,859.25 348,589.80 Yes - -
ORF7a 37,123.79 17,034,560.60 Yes Yes 458.86
4 Discussion
4.1 The novel coronavirus originated from an ancient virus
For the most primitive-life viruses, it isn't very easy to see their role in binding the porphyrin. The
porphyrin compounds are widely present in photosynthetic or non-photosynthetic organisms, and they
are associated with critical physiological processes such as catalysis, oxygen transfer, and energy
transfer. The porphyrin is also an ancient compound widely present on the earth. The porphyrin is first
found in crude oil and asphalt rock in 1934. The porphyrin has unique photoelectronic properties and
excellent thermal stability and has broad application prospects in materials chemistry, medicine,
biochemistry, and analytical chemistry. It is excellent performance in two-photon absorption,
fluorescence effect, energy transfer, and other aspects. Fluorescence resonance energy transfer (FRET)
24. is a non-radiative process in which a donor in an excited state transfers energy to a receptor in the
ground state through a long-range dipole effect. The FRET characteristics of the porphyrin may be the
primary survival mode on which the original virus relied.
There are numerous theories about the origin of viruses, one of which is called co-evolution
theory, which viruses can evolve from complexes of the protein and the nucleic acid . Various methods
do not explain that a virus survived independently of non-appearing cells at the beginning of life, so the
origin of a virus remains a mystery. This paper proposes that a virus could be bind to the porphyrin,
which could explain the survival problem of an original virus. Because the porphyrin has the energy
transfer characteristic of fluorescence resonance, viruses that bind to porphyrins could obtain energy
through this light-induced method. A virus that gained power could achieve minimal displacement
movements, or wake itself from hibernation, or enter hibernation from an active state. Depending on
the research results in this study, the novel coronavirus was a life form dependent on the porphyrin.
Therefore, we could believe that the novel coronavirus originated from an ancient virus that may have
evolved over countless generations in bats.
4.2 Higher permeability of porphyrins into cell membranes leads to high
infections
Highly evolving of the novel coronavirus also displays some paradoxical characteristics. The
current theory suggests that the novel coronavirus binds to the human ACE2 receptor through a spike
protein. It enters human cells in the form of phagocytosis. Infectious disease models indicated that the
novel coronavirus pneumonia is highly contagious. Therefore, the spike protein and human ACE2
protein should have a strong binding ability, but there are reports in the literature that this binding
ability is weak. What causes the high infectivity of the novel coronavirus? We believe that in addition
to the invasive method of spike-ACE2, it should maintain the original invasive pattern.
Medical workers have detected the novel coronavirus from urine, saliva, feces, and blood. The
virus can also live in body fluids. In such media, porphyrin is a prevalent substance. Porphyrin
compounds are a class of nitrogen-containing polymers, and existing studies have found that they have
a strong ability to locate and penetrate cell membranes. At the beginning of life, virus molecules with
porphyrins directly moved into the original membrane structure by porphyrin permeability. This study
showed that the E2 glycoprotein and Envelope protein of the novel coronavirus could bind well to
porphyrins. Therefore, the coronavirus may also directly penetrate the human cell membrane through
porphyrin, so the infection is robust. Our validation analysis showed that Favipiravir could only
prevent the binding of Envelope protein and porphyrin. Meanwhile, chloroquine could effectively
prevent the binding of E2 glycoprotein to porphyrin to a certain extent. Therefore, the infectivity of the
novel coronavirus pneumonia was not completely prevented by the drugs, because of the the binding of
E2 glycoprotein and porphyrin was not inhibited.
4.3 Higher hemoglobin caused higher morbidity
The therapeutic effect of chloroquine phosphate on novel coronavirus pneumonia shows that
novel coronavirus pneumonia might be closely related to abnormal hemoglobin metabolism in humans.
The number of hemoglobin is a major blood biochemical indicator, and the content is different in
different genders. The number of normal men is significantly higher than that of normal women, which
might also be a reason why men are more likely to be infected with the novel coronavirus pneumonia
than women. Besides, patients of novel coronavirus pneumonia are most of the middle-aged and older
adults. Many of these patients have underlying diseases such as diabetes. Diabetic patients have higher
25. glycated hemoglobin. Glycated hemoglobin is deoxyhemoglobin. Glycated hemoglobin is a
combination of hemoglobin and blood glucose, which is another reason for the high infection rate for
older people.
This study has confirmed that orf1ab, ORF3a, and ORF10 could coordinately attack heme on the
beta chain of hemoglobin. Both oxygenated and deoxygenated hemoglobin are attacked. During the
attack, the positions of orf1ab, ORF3, and ORF10 are slightly different. It showed that the higher the
hemoglobin content, the higher the risk of disease. However, it is not sure that the disease rate caused
by abnormal hemoglobin (structural) is relatively low. The hemoglobin of patients and recoverers
should be detected for further research and treatment.
4.4 Inhibiting the heme anabolic pathway and causing the disease
This article considered the virus directly interfered with the assembly of human hemoglobin. The
main reason was the normal heme was too low. Heme joins in critical biological activities such as
regulation of gene expression and protein translation. Porphyrin is an important material for the
synthesis of heme. Because the existing traces show there is too much free iron in the body, it should be
that virus-producing molecule competes with iron for the porphyrin. Inhibiting the heme anabolic
pathway and causing symptoms in humans.
It is not clear whether the spatial molecular structure of heme and porphyrin in patients with
porphyria is the same as that in healthy people. If there is an abnormal structure, it is not clear whether
this porphyrin can bind to a viral protein to form a complex, or if a viral protein can attack this heme. It
should be proved by clinical and experimental research.
4.5 Viral protein infects hemoglobin by the immune hemolysis of red blood cells
Red blood cells mainly contain hemoglobin. During hemolysis, hemoglobin escapes from the
cells and dissolves in the plasma. At this time, the ability of hemoglobin to carry oxygen is lost.
Hemolysis occurs due to rupture of red blood cell membranes and dissolution of the matrix. Or the
expansion of the red cell membrane pores allows hemoglobin to escape, leaving behind a double
concave disc-shaped cell membrane --- "hematocyte". Immune hemolysis is a definite hemolysis
brought about by the antigen-antibody reaction. The non-specific hemolysis is caused by physical,
chemical or biological factors. After hemolysis of red blood cells, viral proteins may infect hemoglobin.
Considering that some researchers have calculated that people with some type O bloods are not easily
infected with COVID-19, we speculate that immune hemolysis may be the main method of viral
protein infection of hemoglobin. Viral proteins attack the hemoglobin after the hemoglobin is infected.
Resulting from limited computational tools, we cannot simulate whether viral proteins attack
hemoglobin outside or inside red blood cells.
4.6 The complexity of individual immunity
Some theories suggest that an immune response occurs in the body after a patient becomes ill.
Some patients develop immune antibodies after recovery. According to this study, E2 glycoprotein,
envelope protein, nucleocapsid phosphoprotein, orf1ab, ORF7a, and ORF8 of the virus could bind to
porphyrin. But from the current research, it is unclear which immune antibodies have been raised
against viral proteins.
Besides, some patients may be killed by their cytokine storm. Comparing to patients with SARs,
the anatomical characteristics of the dead are different. The complex of virus proteins and the
porphyrin may be little soluble. Too much mucus in the tissues of the deceased patients was the cause
26. of too much mucin protein. Mucin could turn loosely connected cells into tightly adhered cells and
increases lubrication between cells. It suggests the compound leads to reduced cell connectivity, and
cells need mucin to consolidate tissue-cell connectivity and lubricity. Also, when a patient enters a
severe infection period, viral structural proteins were mainly used for virus assembly. Therefore, we
cannot find noticeable virus inclusions in tissue cells of the dissected patient.
5 Conclusions
Since the emergency epidemic, it is of high scientific significance to use bioinformatics to analyze
the roles of novel coronavirus proteins (such as ORF8 and surface glycoproteins). In this study, domain
prediction methods were applied to search for conserved domains. The structure of protein molecules
such as ORF8 and surface glycoproteins were obtained using homology modeling methods. Molecular
docking technology was used to analyze the binding part of viral proteins to the heme and the
porphyrin. The study results show that ORF8 and surface glycoproteins could combine to the porphyrin
to form a complex, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could
coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the
porphyrin. The attack will lead to less hemoglobin to carry oxygen and carbon dioxide. The lung cells
have extremely intense inflammation due to the inability to exchange carbon dioxide and oxygen
frequently, which eventually results in ground-glass-like lung images. Patients with respiratory distress
will be made worse. Diabetic patients and older people have higher glycated hemoglobin. Glycated
hemoglobin was reduced by the attack, which made patients' blood sugar unstable. Since the porphyrin
complexes of the virus produced in the human body inhibited the heme anabolic pathway, they caused
a wide range of infection and disease.
With these findings in mind, further analysis revealed that chloroquine could prevent orf1ab,
ORF3a, and ORF10 from attacking the heme to form the porphyrin, and inhibit the binding of ORF8
and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of
respiratory distress. Since the ability of chloroquine to inhibit structural proteins is not particularly
obvious, the therapeutic effect on different people may be different. Favipiravir could inhibit the
envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and
catching free porphyrins. Due to the side effects and allergic reactions of drugs such as chloroquine,
please consult a qualified doctor for treatment details, and do not take the medicine yourself.
This paper is only for academic discussion, the correctness needs to be confirmed by other
laboratories. We look forward to a laboratory that can prove whether this theory is wrong or correct
from the following experiments: 1. Use X-RAY to detect hemoglobin in critically ill patients to find out
if there is any abnormality. 2. It is proved by virus experiments: viral proteins can bind porphyrin; viral
proteins can attack heme; viral proteins can attack hemoglobin in the blood.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
27. Availability of data and materials
The datasets and results supporting the conclusions of this article are available at
https://pan.baidu.com/s/1v8kP0zAyvnACXm-vJHWJuQ, code: rhnb.
Or : https://mega.nz/folder/ciYywQbZ#KjwG5OflNrXTqDpCjWLd1g
Competing interests
The authors declare that they have no competing interests.
Funding
This work was funded by a grant from the Natural Science Foundation for Talent Introduction
Project of Sichuan University of Science and Engineering (award number 2018RCL20, grant recipient
WZL).
Author’s contribution
Funding was obtained by WZL. Design, analysis, writing: WZL. Data curation, check
manuscript: HLL All authors have read and agreed to the published version of the manuscript.
Acknowledgements
Not applicable.
Author details
1
School of Computer Science and Engineering, Sichuan University of Science & Engineering, Zigong, 643002,
China. 2
School of Life Science and Food Engineering, Yibin University, Yibin, 644000, China.
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