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1.
Rev. chil. pediatr ; 91(4): 623-630, ago. 2020.
Article in Spanish | LILACS (Americas) | ID: covidwho-1070235

ABSTRACT

Resumen: SARS-CoV-2 es un virus de alta estabilidad ambiental. Es principalmente un patógeno respiratorio que también afecta el tracto gastrointestinal. El receptor ACE2 es el principal receptor de SARS- CoV-2, hay evidencia de su elevada presencia en intestino, colon y colangiocitos; igualmente se en cuentra expresado en hepatocitos pero en menor proporción. SARS-CoV-2 tiene un tropismo gas trointestinal que explica los síntomas digestivos y la diseminación viral en deposiciones. Las caracte rísticas de SARS-CoV-2 incluyen a la proteína S (Spike o Espícula) que se une de forma muy estable al receptor ACE2. La infección por SARS-CoV-2 produce disbiosis y alteraciones en el eje pulmón- intestino. A nivel intestinal y hepático produce una respuesta Linfocitos T evidente y una respuesta de citocinas que producirían daño intestinal inflamatorio. Las manifestaciones a nivel intestinal en orden de frecuencia son pérdida de apetito, diarrea, náuseas, vómitos y dolor abdominal. Éste último podría ser un marcador de gravedad. En niños la diarrea es habitualmente leve y autolimitada. A nivel hepático la hipertransaminasemia ocurre en 40-60% de los pacientes graves. SARS-CoV-2 puede per manecer en deposiciones un tiempo más prolongado que en secreciones respiratorias, este hallazgo influiría en la diseminación de enfermedad. En esta revisión se destaca la importancia de efectuar un reconocimiento precoz de las manifestaciones gastrointestinales y hepáticas, aumentar el índice de sospecha, efectuar un diagnóstico oportuno y reconocer eventuales complicaciones de la enferme dad. La potencial transmisión fecal oral puede influir en la diseminación de enfermedad. Reconocer este hallazgo es importante para definir aislamiento.


Abstract: SARS-CoV-2 is a high environmental stable virus. It is predominantly a respiratory pathogen that also affects the gastrointestinal tract. The ACE 2 receptor is the main receptor of SARS-CoV-2, with evidence of its high presence in the intestine, colon and cholangiocytes, and, in smaller proportion, in hepatocytes. SARS-CoV-2 has a gastrointestinal tropism that explains digestive symptoms and viral spread in stools. The characteristics of this virus include the S (Spike) protein that binds very stably to the ACE-2 receptor and, at the same time, SARS-CoV-2 produces dysbiosis and alterations in the gut-lung axis. It produces a clear T-cell response and a cytokines storm in the intestine and liver that would produce inflammatory bowel damage. Intestinal manifestations by order of frequency are loss of appetite, diarrhea, nausea and vomiting, and abdominal pain, where the latter could be a severity marker. In children, diarrhea is the most frequent symptom, usually mild and self-limiting. In the liver, hypertransaminasemia occurs in severe patients ranging from 40 to 60%. SARS-CoV-2 can re main in stools longer than in respiratory secretions, which would influence the spread of disease. This article highlights the importance of an early diagnosis of gastrointestinal and hepatic manifestations, increase the index of suspicion, make a timely diagnosis, and recognize eventual complications of the disease. The potential oral-fecal route of transmission may influence the disease spread. Recognizing this finding is important to define isolation.


Subject(s)
Humans , Child , Pneumonia, Viral/complications , Coronavirus Infections/complications , Gastrointestinal Diseases/virology , Liver Diseases/virology , Pneumonia, Viral/diagnosis , Severity of Illness Index , Cytokines/metabolism , Coronavirus Infections/diagnosis , Peptidyl-Dipeptidase A/metabolism , Clinical Laboratory Techniques , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/physiopathology , Liver Diseases/diagnosis , Liver Diseases/physiopathology
2.
Rev. chil. pediatr ; 91(4): 623-630, ago. 2020.
Article in Spanish | LILACS (Americas) | ID: covidwho-1070104

ABSTRACT

Resumen: SARS-CoV-2 es un virus de alta estabilidad ambiental. Es principalmente un patógeno respiratorio que también afecta el tracto gastrointestinal. El receptor ACE2 es el principal receptor de SARS- CoV-2, hay evidencia de su elevada presencia en intestino, colon y colangiocitos; igualmente se en cuentra expresado en hepatocitos pero en menor proporción. SARS-CoV-2 tiene un tropismo gas trointestinal que explica los síntomas digestivos y la diseminación viral en deposiciones. Las caracte rísticas de SARS-CoV-2 incluyen a la proteína S (Spike o Espícula) que se une de forma muy estable al receptor ACE2. La infección por SARS-CoV-2 produce disbiosis y alteraciones en el eje pulmón- intestino. A nivel intestinal y hepático produce una respuesta Linfocitos T evidente y una respuesta de citocinas que producirían daño intestinal inflamatorio. Las manifestaciones a nivel intestinal en orden de frecuencia son pérdida de apetito, diarrea, náuseas, vómitos y dolor abdominal. Éste último podría ser un marcador de gravedad. En niños la diarrea es habitualmente leve y autolimitada. A nivel hepático la hipertransaminasemia ocurre en 40-60% de los pacientes graves. SARS-CoV-2 puede per manecer en deposiciones un tiempo más prolongado que en secreciones respiratorias, este hallazgo influiría en la diseminación de enfermedad. En esta revisión se destaca la importancia de efectuar un reconocimiento precoz de las manifestaciones gastrointestinales y hepáticas, aumentar el índice de sospecha, efectuar un diagnóstico oportuno y reconocer eventuales complicaciones de la enferme dad. La potencial transmisión fecal oral puede influir en la diseminación de enfermedad. Reconocer este hallazgo es importante para definir aislamiento.


Abstract: SARS-CoV-2 is a high environmental stable virus. It is predominantly a respiratory pathogen that also affects the gastrointestinal tract. The ACE 2 receptor is the main receptor of SARS-CoV-2, with evidence of its high presence in the intestine, colon and cholangiocytes, and, in smaller proportion, in hepatocytes. SARS-CoV-2 has a gastrointestinal tropism that explains digestive symptoms and viral spread in stools. The characteristics of this virus include the S (Spike) protein that binds very stably to the ACE-2 receptor and, at the same time, SARS-CoV-2 produces dysbiosis and alterations in the gut-lung axis. It produces a clear T-cell response and a cytokines storm in the intestine and liver that would produce inflammatory bowel damage. Intestinal manifestations by order of frequency are loss of appetite, diarrhea, nausea and vomiting, and abdominal pain, where the latter could be a severity marker. In children, diarrhea is the most frequent symptom, usually mild and self-limiting. In the liver, hypertransaminasemia occurs in severe patients ranging from 40 to 60%. SARS-CoV-2 can re main in stools longer than in respiratory secretions, which would influence the spread of disease. This article highlights the importance of an early diagnosis of gastrointestinal and hepatic manifestations, increase the index of suspicion, make a timely diagnosis, and recognize eventual complications of the disease. The potential oral-fecal route of transmission may influence the disease spread. Recognizing this finding is important to define isolation.


Subject(s)
Humans , Child , Pneumonia, Viral/complications , Coronavirus Infections/complications , Gastrointestinal Diseases/virology , Liver Diseases/virology , Pneumonia, Viral/diagnosis , Severity of Illness Index , Cytokines/metabolism , Coronavirus Infections/diagnosis , Peptidyl-Dipeptidase A/metabolism , Clinical Laboratory Techniques , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/physiopathology , Liver Diseases/diagnosis , Liver Diseases/physiopathology
3.
Clin Sci (Lond) ; 135(3): 535-554, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-1060922

ABSTRACT

The renin-angiotensin system (RAS) has currently attracted increasing attention due to its potential function in regulating energy homeostasis, other than the actions on cellular growth, blood pressure, fluid, and electrolyte balance. The existence of RAS is well established in metabolic organs, including pancreas, liver, skeletal muscle, and adipose tissue, where activation of angiotensin-converting enzyme (ACE) - angiotensin II pathway contributes to the impairment of insulin secretion, glucose transport, fat distribution, and adipokines production. However, the activation of angiotensin-converting enzyme 2 (ACE2) - angiotensin (1-7) pathway, a novel branch of the RAS, plays an opposite role in the ACE pathway, which could reverse these consequences by improving local microcirculation, inflammation, stress state, structure remolding, and insulin signaling pathway. In addition, new studies indicate the protective RAS arm possesses extraordinary ability to enhance brown adipose tissue (BAT) activity and induces browning of white adipose tissue, and consequently, it leads to increased energy expenditure in the form of heat instead of ATP synthesis. Interestingly, ACE2 is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is threating public health worldwide. The main complications of SARS-CoV-2 infected death patients include many energy metabolism-related chronic diseases, such as diabetes. The specific mechanism leading to this phenomenon is largely unknown. Here, we summarize the latest pharmacological and genetic tools on regulating ACE/ACE2 balance and highlight the beneficial effects of the ACE2 pathway axis hyperactivity on glycolipid metabolism, as well as the thermogenic modulation.


Subject(s)
/metabolism , Metabolic Diseases/enzymology , /genetics , Animals , /metabolism , Energy Metabolism , Humans , Metabolic Diseases/genetics , Metabolic Diseases/metabolism , Metabolic Diseases/virology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Renin-Angiotensin System , /physiology
5.
Int J Mol Sci ; 21(16)2020 Aug 07.
Article in English | MEDLINE | ID: covidwho-1024585

ABSTRACT

Gitelman's syndrome (GS) and Bartter's syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature's experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine's ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.


Subject(s)
Bartter Syndrome/genetics , Coronavirus Infections/drug therapy , Gitelman Syndrome/genetics , Peptidyl-Dipeptidase A/metabolism , Phenotype , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Bartter Syndrome/metabolism , Bartter Syndrome/pathology , Endosomes/drug effects , Endosomes/metabolism , Gitelman Syndrome/metabolism , Gitelman Syndrome/pathology , Humans , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Pandemics
6.
J Virol ; 94(20)2020 09 29.
Article in English | MEDLINE | ID: covidwho-1024213

ABSTRACT

The Chinese horseshoe bat (Rhinolophus sinicus), reservoir host of severe acute respiratory syndrome coronavirus (SARS-CoV), carries many bat SARS-related CoVs (SARSr-CoVs) with high genetic diversity, particularly in the spike gene. Despite these variations, some bat SARSr-CoVs can utilize the orthologs of the human SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2), for entry. It is speculated that the interaction between bat ACE2 and SARSr-CoV spike proteins drives diversity. Here, we identified a series of R. sinicus ACE2 variants with some polymorphic sites involved in the interaction with the SARS-CoV spike protein. Pseudoviruses or SARSr-CoVs carrying different spike proteins showed different infection efficiencies in cells transiently expressing bat ACE2 variants. Consistent results were observed by binding affinity assays between SARS-CoV and SARSr-CoV spike proteins and receptor molecules from bats and humans. All tested bat SARSr-CoV spike proteins had a higher binding affinity to human ACE2 than to bat ACE2, although they showed a 10-fold lower binding affinity to human ACE2 compared with that of their SARS-CoV counterpart. Structure modeling revealed that the difference in binding affinity between spike and ACE2 might be caused by the alteration of some key residues in the interface of these two molecules. Molecular evolution analysis indicates that some key residues were under positive selection. These results suggest that the SARSr-CoV spike protein and R. sinicus ACE2 may have coevolved over time and experienced selection pressure from each other, triggering the evolutionary arms race dynamics.IMPORTANCE Evolutionary arms race dynamics shape the diversity of viruses and their receptors. Identification of key residues which are involved in interspecies transmission is important to predict potential pathogen spillover from wildlife to humans. Previously, we have identified genetically diverse SARSr-CoVs in Chinese horseshoe bats. Here, we show the highly polymorphic ACE2 in Chinese horseshoe bat populations. These ACE2 variants support SARS-CoV and SARSr-CoV infection but with different binding affinities to different spike proteins. The higher binding affinity of SARSr-CoV spike to human ACE2 suggests that these viruses have the capacity for spillover to humans. The positive selection of residues at the interface between ACE2 and SARSr-CoV spike protein suggests long-term and ongoing coevolutionary dynamics between them. Continued surveillance of this group of viruses in bats is necessary for the prevention of the next SARS-like disease.


Subject(s)
Biological Coevolution , Chiroptera/virology , SARS Virus/genetics , Spike Glycoprotein, Coronavirus/genetics , Animals , Binding Sites , Chiroptera/classification , Chiroptera/genetics , Coronavirus Infections/virology , Evolution, Molecular , Genetic Variation , HeLa Cells , Humans , Models, Molecular , Mutation , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Phylogeny , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/metabolism , Selection, Genetic , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
9.
J Headache Pain ; 21(1): 38, 2020 Apr 25.
Article in English | MEDLINE | ID: covidwho-1021356

ABSTRACT

The world is currently dominated by the Corona Virus Disease 2019 (COVID-19) pandemic. Besides the obvious concerns about limitation of virus spread and providing the best possible care to infected patients, a concomitant concern has now arisen in view of a putative link between the use of certain drugs, such as Renin-Angiotensin System (RAS) inhibitors and ibuprofen, and an increased risk for COVID-19 infection. We here discuss this concern in relation to headache treatment and conclude that, based on current evidence, there is no reason to abandon treatment of headache patients with RAS inhibitors or ibuprofen.


Subject(s)
Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Coronavirus Infections/pathology , Headache/drug therapy , Ibuprofen/adverse effects , Pneumonia, Viral/pathology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus , Humans , Ibuprofen/therapeutic use , Pandemics , Peptidyl-Dipeptidase A/metabolism , Renin-Angiotensin System , Risk Factors , Up-Regulation/drug effects
10.
Cardiovasc Res ; 116(12): 1932-1936, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-1017764

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) has emerged as a key regulator of the renin-angiotensin system in cardiovascular (CV) disease and plays a pivotal role in infections by coronaviruses and influenza viruses. The present review is primarily focused on the findings to indicate the role of ACE2 in the relationship of coronaviruses and influenza viruses to CV disease. It is postulated that the risk of coronavirus or influenza virus infection is high, at least partly due to high ACE2 expression in populations with a high CV risk. Coronavirus and influenza virus vaccine usage in high CV risk populations could be a potential strategy to prevent both CV disease and coronavirus/influenza virus infections.


Subject(s)
Cardiovascular Diseases/enzymology , Coronavirus Infections/virology , Coronavirus/metabolism , Orthomyxoviridae/metabolism , Peptidyl-Dipeptidase A/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Cardiovascular Diseases/metabolism , Humans
11.
Int J Mol Sci ; 21(24)2020 Dec 16.
Article in English | MEDLINE | ID: covidwho-993550

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is a membrane peptidase and a component of the renin-angiotensin system (RAS) that has been found in cells of all organs, including the lungs. While ACE2 has been identified as the receptor for severe acute respiratory syndrome (SARS) coronaviruses, the mechanism underlying cell entry remains unknown. Human immunodeficiency virus infects target cells via CXC chemokine receptor 4 (CXCR4)-mediated endocytosis. Furthermore, CXCR4 interacts with dipeptidyl peptidase-4 (CD26/DPPIV), an enzyme that cleaves CXCL12/SDF-1, which is the chemokine that activates this receptor. By analogy, we hypothesized that ACE2 might also be capable of interactions with RAS-associated G-protein coupled receptors. Using resonance energy transfer and cAMP and mitogen-activated protein kinase signaling assays, we found that human ACE2 interacts with RAS-related receptors, namely the angiotensin II type 1 receptor (AT1R), the angiotensin II type 2 receptor (AT2R), and the MAS1 oncogene receptor (MasR). Although these interactions lead to minor alterations of signal transduction, ligand binding to AT1R and AT2R, but not to MasR, resulted in the upregulation of ACE2 cell surface expression. Proximity ligation assays performed in situ revealed macromolecular complexes containing ACE2 and AT1R, AT2R or MasR in adult but not fetal mouse lung tissue. These findings highlight the relevance of RAS in SARS-CoV-2 infection and the role of ACE2-containing complexes as potential therapeutic targets.


Subject(s)
/metabolism , Receptors, CXCR4/metabolism , Receptors, Virus/metabolism , /metabolism , Adult , Cell Line , Chemokine CXCL12/metabolism , HEK293 Cells , Humans , Peptidyl-Dipeptidase A/metabolism , Proto-Oncogene Proteins/metabolism , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/metabolism , Receptors, G-Protein-Coupled/metabolism , Renin-Angiotensin System/physiology , Signal Transduction/physiology
12.
Cells ; 9(11)2020 10 22.
Article in English | MEDLINE | ID: covidwho-983193

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the Coronavirus disease (COVID-19) pandemic, has so far resulted in more than 1.1 M deaths and 40 M cases worldwide with no confirmed remedy yet available. Since the first outbreak in Wuhan, China in December 2019, researchers across the globe have been in a race to develop therapies and vaccines against the disease. SARS-CoV-2, similar to other previously identified Coronaviridae family members, encodes several structural proteins, such as spike, envelope, membrane, and nucleocapsid, that are responsible for host penetration, binding, recycling, and pathogenesis. Structural biology has been a key player in understanding the viral infection mechanism and in developing intervention strategies against the new coronavirus. The spike glycoprotein has drawn considerable attention as a means to block viral entry owing to its interactions with the human angiotensin-converting enzyme 2 (ACE2), which acts as a receptor. Here, we review the current knowledge of SARS-CoV-2 and its interactions with ACE2 and antibodies. Structural information of SARS-CoV-2 spike glycoprotein and its complexes with ACE2 and antibodies can provide key input for the development of therapies and vaccines against the new coronavirus.


Subject(s)
Betacoronavirus/chemistry , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Binding Sites , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Humans , Pandemics/prevention & control , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , Protein Binding , Protein Domains/immunology , Spike Glycoprotein, Coronavirus/metabolism
13.
Zool Res ; 41(6): 621-631, 2020 11 18.
Article in English | MEDLINE | ID: covidwho-982982

ABSTRACT

Understanding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clarifying antiviral immunity in hosts are critical aspects for the development of vaccines and antivirals. Mice are frequently used to generate animal models of infectious diseases due to their convenience and ability to undergo genetic manipulation. However, normal adult mice are not susceptible to SARS-CoV-2. Here, we developed a viral receptor (human angiotensin-converting enzyme 2, hACE2) pulmonary transfection mouse model to establish SARS-CoV-2 infection rapidly in the mouse lung. Based on the model, the virus successfully infected the mouse lung 2 days after transfection. Viral RNA/protein, innate immune cell infiltration, inflammatory cytokine expression, and pathological changes in the infected lungs were observed after infection. Further studies indicated that neutrophils were the first and most abundant leukocytes to infiltrate the infected lungs after viral infection. In addition, using infected CXCL5-knockout mice, chemokine CXCL5 was responsible for neutrophil recruitment. CXCL5 knockout decreased lung inflammation without diminishing viral clearance, suggesting a potential target for controlling pneumonia.


Subject(s)
Betacoronavirus/immunology , Chemokine CXCL5/immunology , Coronavirus Infections/immunology , Immunity, Innate/immunology , Neutrophils/immunology , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/immunology , Animals , Betacoronavirus/genetics , Betacoronavirus/physiology , Cell Line , Chemokine CXCL5/genetics , Chemokine CXCL5/metabolism , Coronavirus Infections/genetics , Coronavirus Infections/virology , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Humans , Male , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neutrophils/metabolism , Neutrophils/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/genetics , Pneumonia, Viral/virology
14.
Molecules ; 25(11)2020 Jun 11.
Article in English | MEDLINE | ID: covidwho-981163

ABSTRACT

Flavonoids are widely used as phytomedicines. Here, we report on flavonoid phytomedicines with potential for development into prophylactics or therapeutics against coronavirus disease 2019 (COVID-19). These flavonoid-based phytomedicines include: caflanone, Equivir, hesperetin, myricetin, and Linebacker. Our in silico studies show that these flavonoid-based molecules can bind with high affinity to the spike protein, helicase, and protease sites on the ACE2 receptor used by the severe acute respiratory syndrome coronavirus 2 to infect cells and cause COVID-19. Meanwhile, in vitro studies show potential of caflanone to inhibit virus entry factors including, ABL-2, cathepsin L, cytokines (IL-1ß, IL-6, IL-8, Mip-1α, TNF-α), and PI4Kiiiß as well as AXL-2, which facilitates mother-to-fetus transmission of coronavirus. The potential for the use of smart drug delivery technologies like nanoparticle drones loaded with these phytomedicines to overcome bioavailability limitations and improve therapeutic efficacy are discussed.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus OC43, Human/drug effects , Flavonoids/pharmacology , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/chemistry , Animals , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Betacoronavirus/growth & development , Binding Sites , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/genetics , Coronavirus OC43, Human/chemistry , Coronavirus OC43, Human/growth & development , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Flavonoids/chemistry , Humans , Interleukins/antagonists & inhibitors , Interleukins/chemistry , Interleukins/genetics , Interleukins/metabolism , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Lung/drug effects , Lung/pathology , Lung/virology , Mice , Molecular Docking Simulation , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Phytotherapy/methods , Pneumonia, Viral/genetics , Primary Cell Culture , Protein Binding , Protein Interaction Domains and Motifs , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics , Virus Internalization/drug effects
16.
Cells ; 9(11)2020 10 27.
Article in English | MEDLINE | ID: covidwho-972335

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has sparked a global pandemic of the coronavirus disease of 2019 (COVID-19). The virus invades human cells through the angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway, primarily targeting the human respiratory tract. However, emerging reports of neurological manifestations demonstrate the neuroinvasive potential of SARS-CoV-2. This review highlights the possible routes by which SARS-CoV-2 may invade the central nervous system (CNS) and provides insight into recent case reports of COVID-19-associated neurological disorders, namely ischaemic stroke, encephalitis, encephalopathy, epilepsy, neurodegenerative diseases, and inflammatory-mediated neurological disorders. We hypothesize that SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may be implicated in the development of the observed disorders; however, further research is critical to understand the detailed mechanisms and pathway of infectivity behind CNS pathogenesis.


Subject(s)
Betacoronavirus/metabolism , Blood-Brain Barrier/physiopathology , Blood-Brain Barrier/virology , Coronavirus Infections/complications , Nervous System Diseases/complications , Pneumonia, Viral/complications , Virus Internalization , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/metabolism , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/virology
17.
Eur Rev Med Pharmacol Sci ; 24(21): 11409-11420, 2020 11.
Article in English | MEDLINE | ID: covidwho-937848

ABSTRACT

OBJECTIVE: Diabetes is a lifestyle disease and it has become an epidemic worldwide in recent decades. In the ongoing COVID-19 pandemic situation, diabetes has become a serious health concern since large numbers of patients are vulnerable to die from the virus. Thus, diabetic patients affected by COVID-19 cause a major health crisis now. Reports show that large occurrence of diabetes makes it a serious comorbidity in COVID-19 patients. MATERIALS AND METHODS: It is crucial to understand how COVID-19 affects diabetes patients. This paper has reviewed published literature extensively to understand the pattern, importance, care, and medication. RESULTS: This review summarizes the association between COVID-19 and diabetes in terms of susceptibility for pneumonia and other diseases. It also discusses the harshness of COVID-19 with diabetes populations and immunological impacts. It further adds the ACE2 receptor role in diabetes with COVID-19 patients. CONCLUSIONS: Finally, this paper illustrates different types of diabetes management techniques, such as blood glucose management, self-management, mental health management, and therapeutic management. It also summarizes the current knowledge about diabetic patients with COVID-19 to fight this pandemic.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Disease Susceptibility/immunology , Pneumonia, Viral/immunology , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , Blood Glucose/drug effects , Blood Glucose/metabolism , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/immunology , Humans , Hypoglycemic Agents/administration & dosage , Pancreas/pathology , Pandemics/prevention & control , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Severity of Illness Index , Spike Glycoprotein, Coronavirus/metabolism , Virus Replication/immunology
18.
J Proteome Res ; 19(11): 4576-4586, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-936108

ABSTRACT

SARS-CoV-2 has caused the largest pandemic of the twenty-first century (COVID-19), threatening the life and economy of all countries in the world. The identification of novel therapies and vaccines that can mitigate or control this global health threat is among the most important challenges facing biomedical sciences. To construct a long-term strategy to fight both SARS-CoV-2 and other possible future threats from coronaviruses, it is critical to understand the molecular mechanisms underlying the virus action. The viral entry and associated infectivity stems from the formation of the SARS-CoV-2 spike protein complex with angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein molecule can be used to elucidate the molecular pathways that can be targeted with allosteric drugs to weaken the spike-ACE2 interaction and, thus, reduce viral infectivity. In this study, we present the results of the application of different computational methods aimed at detecting allosteric sites on the SARS-CoV-2 spike protein. The adopted tools consisted of the protein contact networks (PCNs), SEPAS (Affinity by Flexibility), and perturbation response scanning (PRS) based on elastic network modes. All of these methods were applied to the ACE2 complex with both the SARS-CoV2 and SARS-CoV spike proteins. All of the adopted analyses converged toward a specific region (allosteric modulation region [AMR]), present in both complexes and predicted to act as an allosteric site modulating the binding of the spike protein with ACE2. Preliminary results on hepcidin (a molecule with strong structural and sequence with AMR) indicated an inhibitory effect on the binding affinity of the spike protein toward the ACE2 protein.


Subject(s)
Allosteric Site/genetics , Coronavirus Infections/virology , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus , Betacoronavirus/genetics , Binding Sites , Drug Discovery , Humans , Models, Molecular , Neural Networks, Computer , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
19.
Clin Sci (Lond) ; 134(22): 2987-3006, 2020 11 27.
Article in English | MEDLINE | ID: covidwho-933737

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin-angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Pneumonia, Viral/virology , Receptor, Angiotensin, Type 2/agonists , ras Proteins/metabolism , Coronavirus Infections/drug therapy , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology
20.
Nat Commun ; 11(1): 5752, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-926678

ABSTRACT

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, with SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with FcγRIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity is eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Potent prophylactic and therapeutic effects against SARS-CoV-2 are observed in rhesus monkeys. A single dose of MW05/LALA blocks infection of SARS-CoV-2 in prophylactic treatment and clears SARS-CoV-2 in three days in a therapeutic treatment setting. These results pave the way for the development of MW05/LALA as an antiviral strategy for COVID-19.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antiviral Agents/pharmacology , Betacoronavirus/immunology , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Viral/immunology , Cell Line , Chlorocebus aethiops , Coronavirus Infections/prevention & control , Female , HEK293 Cells , Humans , Macaca mulatta , Male , Pandemics/prevention & control , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/prevention & control , Receptors, IgG/genetics , Receptors, IgG/immunology , Receptors, Virus/metabolism , Vero Cells , Virus Attachment
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