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1.
PLoS One ; 16(6): e0253489, 2021.
Article in English | MEDLINE | ID: covidwho-1388925

ABSTRACT

In the pursuit of suitable and effective solutions to SARS-CoV-2 infection, we investigated the efficacy of several phenolic compounds in controlling key cellular mechanisms involved in its infectivity. The way the SARS-CoV-2 virus infects the cell is a complex process and comprises four main stages: attachment to the cognate receptor, cellular entry, replication and cellular egress. Since, this is a multi-part process, it creates many opportunities to develop effective interventions. Targeting binding of the virus to the host receptor in order to prevent its entry has been of particular interest. Here, we provide experimental evidence that, among 56 tested polyphenols, including plant extracts, brazilin, theaflavin-3,3'-digallate, and curcumin displayed the highest binding with the receptor-binding domain of spike protein, inhibiting viral attachment to the human angiotensin-converting enzyme 2 receptor, and thus cellular entry of pseudo-typed SARS-CoV-2 virions. Both, theaflavin-3,3'-digallate at 25 µg/ml and curcumin above 10 µg/ml concentration, showed binding with the angiotensin-converting enzyme 2 receptor reducing at the same time its activity in both cell-free and cell-based assays. Our study also demonstrates that brazilin and theaflavin-3,3'-digallate, and to a still greater extent, curcumin, decrease the activity of transmembrane serine protease 2 both in cell-free and cell-based assays. Similar pattern was observed with cathepsin L, although only theaflavin-3,3'-digallate showed a modest diminution of cathepsin L expression at protein level. Finally, each of these three compounds moderately increased endosomal/lysosomal pH. In conclusion, this study demonstrates pleiotropic anti-SARS-CoV-2 efficacy of specific polyphenols and their prospects for further scientific and clinical investigations.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/prevention & control , Polyphenols/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , A549 Cells , Benzopyrans/pharmacology , Biflavonoids/pharmacology , COVID-19/virology , Catechin/analogs & derivatives , Catechin/pharmacology , Cell Survival/drug effects , Curcumin/pharmacology , Humans , Protein Binding/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Virion/drug effects , Virion/metabolism , Virion/physiology , Virus Attachment/drug effects
3.
Sci Rep ; 11(1): 12787, 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1275960

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19) has resulted in a pandemic affecting the most vulnerable in society, triggering a public health crisis and economic collapse around the world. Effective treatments to mitigate this viral infection are needed. Since the eye is a route of virus entrance, we use an in vivo rat model of corneal inflammation as well as human corneal epithelial cells (HCEC) in culture challenged with IFNγ as models of the eye surface to study this issue. We explore ways to block the receptor-binding domain (RBD) of SARS-CoV-2 Spike (S) protein to angiotensin-converting enzyme 2 (ACE2). We found that the lipid mediators, elovanoid (ELV)-N32 or Resolvin D6-isomer (RvD6i) decreased the expression of the ACE2 receptor, furin, and integrins in damaged corneas or IFNγ-stimulated HCEC. There was also a concomitant decrease in the binding of Spike RBD with the lipid treatments. Using RNA-seq analysis, we uncovered that the lipid mediators also attenuated the expression of pro-inflammatoy cytokines participating in hyper-inflammation and senescence programming. Thus, the bioactivity of these lipid mediators will contribute to open therapeutic avenues to counteract virus attachment and entrance to the body.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Cellular Senescence/drug effects , Corneal Injuries/metabolism , Cytokines/metabolism , Docosahexaenoic Acids/analogs & derivatives , Docosahexaenoic Acids/pharmacology , Drug Discovery/methods , Protein Domains , Signal Transduction/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Animals , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Disease Models, Animal , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelium, Corneal/cytology , Humans , Lipoxins/pharmacology , Male , Protein Binding , Rats , Rats, Sprague-Dawley , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Virus Attachment/drug effects , Virus Internalization/drug effects
4.
Cell Signal ; 85: 110064, 2021 09.
Article in English | MEDLINE | ID: covidwho-1272329

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019, it binds to angiotensin-converting enzyme 2 (ACE2) to enter into human cells. The expression level of ACE2 potentially determine the susceptibility and severity of COVID-19, it is thus of importance to understand the regulatory mechanism of ACE2 expression. Tripartite motif containing 28 (TRIM28) is known to be involved in multiple processes including antiviral restriction, endogenous retrovirus latency and immune response, it is recently reported to be co-expressed with SARS-CoV-2 receptor in type II pneumocytes; however, the roles of TRIM28 in ACE2 expression and SARS-CoV-2 cell entry remain unclear. This study showed that knockdown of TRIM28 induces ACE2 expression and increases pseudotyped SARS-CoV-2 cell entry of A549 cells and primary pulmonary alveolar epithelial cells (PAEpiCs). In a co-culture model of NK cells and lung epithelial cells, our results demonstrated that NK cells inhibit TRIM28 and promote ACE2 expression in lung epithelial cells, which was partially reversed by depletion of interleukin-2 and blocking of granzyme B in the co-culture medium. Furthermore, TRIM28 knockdown enhanced interferon-γ (IFN-γ)- induced ACE2 expression through a mechanism involving upregulating IFN-γ receptor 2 (IFNGR2) in both A549 and PAEpiCs. The upregulated ACE2 induced by TRIM28 knockdown and co-culture of NK cells was partially reversed by dexamethasone in A549 cells. Our study identified TRIM28 as a novel regulator of ACE2 expression and SARS-CoV-2 cell entry.


Subject(s)
Angiotensin-Converting Enzyme 2/drug effects , Antiviral Agents/pharmacology , SARS-CoV-2/pathogenicity , Tripartite Motif-Containing Protein 28/immunology , Virus Internalization/drug effects , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/immunology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Lung/metabolism , Lung/virology , Peptidyl-Dipeptidase A/metabolism , Tripartite Motif-Containing Protein 28/drug effects
5.
Clin Infect Dis ; 72(11): e736-e741, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1249285

ABSTRACT

BACKGROUND: A local increase in angiotensin 2 after inactivation of angiotensin-converting enzyme 2 by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce a redox imbalance in alveolar epithelium cells, causing apoptosis, increased inflammation and, consequently, impaired gas exchange. We hypothesized that N-acetylcysteine (NAC) administration could restore this redox homeostasis and suppress unfavorable evolution in patients with coronavirus disease 2019 (COVID-19). METHODS: This was a double-blind, randomized, placebo-controlled, single-center trial conducted at the Emergency Department of Hospital das Clínicas, São Paulo, Brazil, to determine whether NAC in high doses can avoid respiratory failure in patients with COVID-19. We enrolled 135 patients with severe COVID-19 (confirmed or suspected), with an oxyhemoglobin saturation <94% or respiratory rate >24 breaths/minute. Patients were randomized to receive NAC 21 g (~300 mg/kg) for 20 hours or dextrose 5%. The primary endpoint was the need for mechanical ventilation. Secondary endpoints were time of mechanical ventilation, admission to the intensive care unit (ICU), time in ICU, and mortality. RESULTS: Baseline characteristics were similar between the 2 groups, with no significant differences in age, sex, comorbidities, medicines taken, and disease severity. Also, groups were similar in laboratory tests and chest computed tomography scan findings. Sixteen patients (23.9%) in the placebo group received endotracheal intubation and mechanical ventilation, compared with 14 patients (20.6%) in the NAC group (P = .675). No difference was observed in secondary endpoints. CONCLUSIONS: Administration of NAC in high doses did not affect the evolution of severe COVID-19. CLINICAL TRIALS REGISTRATION: Brazilian Registry of Clinical Trials (REBEC): U1111-1250-356 (http://www.ensaiosclinicos.gov.br/rg/RBR-8969zg/).


Subject(s)
COVID-19 , Acetylcysteine/therapeutic use , Brazil , COVID-19/drug therapy , Double-Blind Method , Humans , Respiration, Artificial , SARS-CoV-2 , Treatment Outcome
7.
Mol Med ; 27(1): 49, 2021 05 22.
Article in English | MEDLINE | ID: covidwho-1238700

ABSTRACT

A SARS-like coronavirus 2 (SARS-CoV-2) has caused a pandemic Coronavirus Disease 2019 (COVID-19) that killed more than 3.3 million people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its spike protein to bind a host receptor, the angiotensin-converting enzyme 2 (ACE2), to gain entry. Currently, several mRNA or adenoviral vaccines encoding for the spike protein of SARS-CoV-2 are being used to boost antibodies capable of inhibiting spike-ACE2 interaction and viral entry. However, recent evidence has also suggested an anti-inflammatory effect of spike-reactive antibodies, suggesting that some SARS-CoV-2 spike-based vaccines may elicit protective antibodies capable of inhibiting GM-CSF production and COVID-19 progression.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/metabolism , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Antibodies, Neutralizing/immunology , COVID-19/metabolism , COVID-19/virology , COVID-19 Vaccines/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Host-Pathogen Interactions/drug effects , Humans , Protein Binding/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Virus Internalization/drug effects , Virus Replication/drug effects
8.
Int J Mol Sci ; 22(10)2021 May 16.
Article in English | MEDLINE | ID: covidwho-1234743

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and ß-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4+ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4+ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin-angiotensin-aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill's causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19.


Subject(s)
Adaptive Immunity , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , Immunity, Innate , SARS-CoV-2/immunology , Vitamin D/metabolism , Vitamin D/pharmacology , COVID-19/mortality , COVID-19/physiopathology , COVID-19/virology , Cytokine Release Syndrome/complications , Cytokines/metabolism , Humans , Receptors, Virus/metabolism , Renin-Angiotensin System/physiology
9.
Int J Cardiol ; 336: 123-129, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1230514

ABSTRACT

BACKGROUND: Angiotensin converting enzyme 2 (ACE2) has recently been identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent response for novel coronavirus disease 2019 (COVID-19). This study aimed to explore the roles of ACE2, apelin and sodium-glucose cotransporter 2 (SGLT2) in SARS-CoV-2-mediated cardiorenal damage. METHODS AND RESULTS: The published RNA-sequencing datasets of cardiomyocytes infected with SARS-CoV-2 and COVID-19 patients were used. String, UMAP plots and single cell RNA sequencing data were analyzed to show the close relationship and distinct cardiorenal distribution patterns of ACE2, apelin and SGLT2. Intriguingly, there were decreases in ACE2 and apelin expression as well as marked increases in SGLT2 and endothelin-1 levels in SARS-CoV-2-infected cardiomyocytes, animal models with diabetes, acute kidney injury, heart failure and COVID-19 patients. These changes were linked with downregulated levels of interleukin (IL)-10, superoxide dismutase 2 and catalase as well as upregulated expression of profibrotic genes and pro-inflammatory cytokines/chemokines. Genetic ACE2 deletion resulted in upregulation of pro-inflammatory cytokines containing IL-1ß, IL-6, IL-17 and tumor necrosis factor α. More importantly, dapagliflozin strikingly alleviated cardiorenal fibrosis in diabetic db/db mice by suppressing SGLT2 levels and potentiating the apelin-ACE2 signaling. CONCLUSION: Downregulation of apelin and ACE2 and upregulation of SGLT2, endothelin-1 and pro-inflammatory cytokines contribute to SARS-CoV-2-mediated cardiorenal injury, indicating that the apelin-ACE2 signaling and SGLT2 inhibitors are potential therapeutic targets for COVID-19 patients.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Animals , Apelin , Humans , Mice , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Sodium-Glucose Transporter 2
10.
Front Cell Infect Microbiol ; 11: 655666, 2021.
Article in English | MEDLINE | ID: covidwho-1226972

ABSTRACT

Background: From the first detection in 2019, SARS-CoV-2 infections have spread rapidly worldwide and have been proven to cause an urgent and important health problem. SARS-CoV-2 cell entry depends on two proteins present on the surface of host cells, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). The nasal cavity is thought to be one of the initial sites of infection and a possible reservoir for dissemination within and between individuals. However, it is not known how the expression of these genes is regulated in the nasal mucosa. Objective: In this study, we examined whether the expression of ACE2 and TMPRSS2 is affected by innate immune signals in the nasal mucosa. We also investigated how fluticasone propionate (FP), a corticosteroid used as an intranasal steroid spray, affects the gene expression. Methods: Primary human nasal epithelial cells (HNECs) were collected from the nasal mucosa and incubated with Toll-like receptor (TLR) agonists and/or fluticasone propionate (FP), followed by quantitative PCR, immunofluorescence, and immunoblot analyses. Results: Among the TLR agonists, the TLR3 agonist Poly(I:C) significantly increased ACE2 and TMPRSS2 mRNA expression in HNECs (ACE2 36.212±11.600-fold change, p<0.0001; TMPRSS2 5.598±2.434-fold change, p=0.031). The ACE2 protein level was also increased with Poly(I:C) stimulation (2.884±0.505-fold change, p=0.003). The Poly(I:C)-induced ACE2 expression was suppressed by co-incubation with FP (0.405±0.312-fold change, p=0.044). Conclusion: The activation of innate immune signals via TLR3 promotes the expression of genes related to SARS-CoV2 cell entry in the nasal mucosa, although this expression is suppressed in the presence of FP. Further studies are required to evaluate whether FP suppresses SARS-CoV-2 viral cell entry.


Subject(s)
COVID-19 , Peptidyl-Dipeptidase A , Angiotensin-Converting Enzyme 2 , Epithelial Cells , Fluticasone , Humans , Peptidyl-Dipeptidase A/genetics , RNA, Viral , SARS-CoV-2
11.
Turk J Med Sci ; 51(4): 1659-1664, 2021 08 30.
Article in English | MEDLINE | ID: covidwho-1218646

ABSTRACT

Background/aim: SARS-CoV-2 enters the cell through the binding of the S glycoprotein on the surface of the virus to the angiotensin- converting enzyme 2 (ACE-2) in the host cells and also SARS-CoV S protein binding to ACE-2 was inhibited by anti-A antibodies. The aim of the study was to investigate the relationship between blood groups and the course of COVID-19 in Turkey. Materials and methods: Laboratory confirmed COVID-19 patients aged 18 and over (n = 39.850) were randomized in age and sex- matched groups according to blood groups. Results: Advanced age, male sex and blood group A were found to be related with increased rate of intensive care unit (ICU) admission (OR = 1.089, 95% CI: 1.085­1.093 for age; OR = 1.963, 95% CI: 1.737­2.218 for male sex; OR = 1.216, 95% CI: 1.023­1.446 for blood group A). When blood group O individuals were compared to non-O individuals, no significant difference was observed regarding the rate of hospital and ICU admission, mechanical ventilation (MV) support, length of hospital and ICU stay, and case fatality rate (CFR). The CFR in patients with blood group A, B, O, and AB were 2.6%, 2.2%, 3.1%, and 2.3%, respectively. There were no significant differences between Rh-negative and positive patients regarding the rate of hospital and ICU admission (p = 0.280 and p = 0.741, respectively), also the rate of MV support and CFR was similar (p = 0.933 and p = 0.417). Conclusion: Our study revealed that ABO and Rh blood groups do not have any impact on the rate of hospital admission, hospital and ICU stay, MV support, and CFR.


Subject(s)
Blood Group Antigens/blood , COVID-19/blood , COVID-19/epidemiology , Critical Care/statistics & numerical data , Hospitalization/statistics & numerical data , Respiration, Artificial/statistics & numerical data , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/pathology , Female , Humans , Intensive Care Units/statistics & numerical data , Length of Stay/statistics & numerical data , Male , Middle Aged , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Sex Factors , Turkey/epidemiology , Young Adult
12.
IEEE/ACM Trans Comput Biol Bioinform ; 18(4): 1271-1280, 2021.
Article in English | MEDLINE | ID: covidwho-1199626

ABSTRACT

COVID-19 is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The case-fatality rate is significantly higher in older patients and those with diabetes, cancer or cardiovascular disorders. The human proteins, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2) and basigin (BSG), are involved in high-confidence host-pathogen interactions with SARS-CoV-2 proteins. We considered these three proteins as seed nodes and applied the random walk with restart method on the human interactome to construct a protein-protein interaction sub-network, which captures the effects of viral invasion. We found that 'Insulin resistance', 'AGE-RAGE signaling in diabetic complications' and 'adipocytokine signaling' were the common pathways associated with diabetes, cancer and cardiovascular disorders. The association of these critical pathways with aging and its related diseases explains the molecular basis of COVID-19 fatality. We further identified drugs that have effects on these proteins/pathways based on gene expression studies. We particularly focused on drugs that significantly downregulate ACE2 along with other critical proteins identified by the network-based approach. Among them, COL-3 had earlier shown activity against acute lung injury and acute respiratory distress, while entinostat and mocetinostat have been investigated for non-small-cell lung cancer. We propose that these drugs can be repurposed for COVID-19.


Subject(s)
COVID-19/mortality , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/therapy , Cardiovascular Diseases/epidemiology , Comorbidity , Computational Biology , Drug Repositioning , Gastrointestinal Diseases/epidemiology , Gene Expression Profiling/statistics & numerical data , Host Microbial Interactions/drug effects , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Pandemics , Protein Interaction Maps/drug effects , Respiratory Tract Diseases/epidemiology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology
13.
Clin Sci (Lond) ; 135(8): 1009-1014, 2021 04 30.
Article in English | MEDLINE | ID: covidwho-1195632

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is the leading player of the protective renin-angiotensin system (RAS) pathway but also the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAS inhibitors seemed to interfere with the ACE2 receptor, and their safety was addressed in COVID-19 patients. Pedrosa et al. (Clin. Sci. (Lond.) (2021), 135, 465-481) showed in rats that captopril and candesartan up-regulated ACE2 expression and the protective RAS pathway in lung tissue. In culture of pneumocytes, the captopril/candesartan-induced ACE2 up-regulation was associated with inhibition of ADAM17 activity, counterbalancing increased ACE2 expression, which was associated with reduced SARS-CoV-2 spike protein entry. If confirmed in humans, these results could become the pathophysiological background for justifying RAS inhibitors as cornerstone cardiovascular protectives even during COVID-19 pandemic.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , COVID-19 , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Benzimidazoles , Biphenyl Compounds , Captopril/pharmacology , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Rats , Renin-Angiotensin System , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Tetrazoles
14.
Biomedicines ; 9(4)2021 Apr 18.
Article in English | MEDLINE | ID: covidwho-1194606

ABSTRACT

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

15.
Nutrients ; 13(4)2021 Apr 14.
Article in English | MEDLINE | ID: covidwho-1187014

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for one of the worst pandemics in modern history. Several prevention and treatment strategies have been designed and evaluated in recent months either through the repurposing of existing treatments or the development of new drugs and vaccines. In this study, we show that L-carnitine tartrate supplementation in humans and rodents led to significant decreases of key host dependency factors, notably angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and Furin, which are responsible for viral attachment, viral spike S-protein cleavage, and priming for viral fusion and entry. Interestingly, pre-treatment of Calu-3, human lung epithelial cells, with L-carnitine tartrate led to a significant and dose-dependent inhibition of the infection by SARS-CoV-2. Infection inhibition coincided with a significant decrease in ACE2 mRNA expression levels. These data suggest that L-carnitine tartrate should be tested with appropriate trials in humans for the possibility to limit SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Carnitine/administration & dosage , Tartrates/administration & dosage , Adult , Aged , Angiotensin-Converting Enzyme 2/blood , Animals , COVID-19/metabolism , Carnitine/pharmacology , Cell Line , Cell Survival/drug effects , Female , Furin/blood , Furin/metabolism , Humans , Inflammation/metabolism , Male , Middle Aged , Rats , SARS-CoV-2 , Serine Endopeptidases/blood , Serine Endopeptidases/metabolism , Tartrates/pharmacology , Young Adult
16.
Cell Rep ; 35(3): 109020, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1182447

ABSTRACT

COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment, and one important factor to consider is oxygen tension, in which hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its spike glycoprotein binding to angiotensin-converting enzyme 2 (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via an HIF-1α-dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication, showing that post-entry steps in the viral life cycle are oxygen sensitive. This study highlights the importance of HIF signaling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19.


Subject(s)
COVID-19/metabolism , Epithelial Cells/metabolism , Glycine/analogs & derivatives , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Isoquinolines/pharmacology , Lung/metabolism , SARS-CoV-2/physiology , Virus Internalization/drug effects , Virus Replication/drug effects , A549 Cells , Animals , COVID-19/drug therapy , COVID-19/pathology , Caco-2 Cells , Cell Hypoxia/drug effects , Chlorocebus aethiops , Epithelial Cells/virology , Glycine/pharmacology , Humans , Lung/virology , Mice , Vero Cells
17.
J Biomol Struct Dyn ; : 1-14, 2021 Apr 02.
Article in English | MEDLINE | ID: covidwho-1165102

ABSTRACT

SARS-CoV-2 outbreak in China in December 2019 and its spread as worldwide pandemic has been a major global health crisis. Extremely high infection and mortality rate has severely affected all sectors of life and derailed the global economy. While drug and vaccine development have been prioritized and have made significant progression, use of phytochemicals and herbal constituents is deemed as a low-cost, safer and readily available alternative. We investigated therapeutic efficacy of eight withanolides (derived from Ashwagandha) against the angiotensin-converting enzyme 2 (ACE2) proteins, a target cell surface receptor for SARS-CoV-2 and report results on the (i) computational analyses including binding affinity and stable interactions with ACE2, occupancy of ACE2 residues in making polar and nonpolar interactions with different withanolides/ligands and (2) in vitro mRNA and protein analyses using human cancer (A549, MCF7 and HSC3) cells. We found that among all withanolides, Withaferin-A, Withanone, Withanoside-IV and Withanoside-V significantly inhibited the ACE2 expression. Analysis of withanolides-rich aqueous extracts derived from Ashwagandha leaves and stem showed a higher ACE2 inhibitory potency of stem-derived extracts. Taken together, we demonstrated the inhibitory potency of Ashwagandha withanolides and its aqueous extracts against ACE2.Communicated by Ramaswamy H. Sarma.

18.
J Leukoc Biol ; 111(1): 261-267, 2022 01.
Article in English | MEDLINE | ID: covidwho-1147560

ABSTRACT

A severe acute respiratory syndrome (SARS)-like coronavirus 2 (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected approximately 94 million and killed more than 2,000,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibodies that can inhibit virus-ACE2 interaction to prevent viral entry. It was previously unknown how spike protein-targeting antibodies would affect innate inflammatory responses to SARS-CoV-2 infections. Here we generated a highly purified recombinant protein corresponding to the RBM of SARS-CoV-2, and used it to screen for cross-reactive monoclonal antibodies (mAbs). We found two RBM-binding mAbs that competitively inhibited its interaction with human ACE2, and specifically blocked the RBM-induced GM-CSF secretion in both human peripheral blood mononuclear cells and murine macrophage cultures. Our findings have suggested a possible strategy to prevent SARS-CoV-2-elicited "cytokine storm," and revealed a potentially anti-inflammatory and protective mechanism for SARS-CoV-2 spike-based vaccines.


Subject(s)
Antibodies, Monoclonal/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Motifs , Angiotensin-Converting Enzyme 2/metabolism , Animals , Humans , Leukocytes, Mononuclear/metabolism , Macrophages/metabolism , Mice , Protein Binding , RAW 264.7 Cells , Recombinant Proteins/metabolism
19.
Exp Ther Med ; 21(5): 441, 2021 May.
Article in English | MEDLINE | ID: covidwho-1145635

ABSTRACT

Acid preconditioning (APC) through carbon dioxide inhalation can exert protective effects during acute lung injury (ALI) triggered by ischemia-reperfusion. Angiotensin-converting enzyme 2 (ACE2) has been identified as a receptor for severe acute respiratory syndrome coronavirus and the novel coronavirus disease-19. Downregulation of ACE2 plays an important role in the pathogenesis of severe lung failure after viral or bacterial infections. The aim of the present study was to examine the anti-inflammatory mechanism through which APC alleviates lipopolysaccharide (LPS)-induced ALI in vivo and in vitro. The present results demonstrated that LPS significantly downregulated the expression of ACE2, while APC significantly reduced LPS-induced ALI and provided beneficial effects. In addition, bioinformatics analysis indicated that microRNA (miR)-200c-3p directly targeted the 3'untranslated region of ACE2 and regulated the expression of ACE2 protein. LPS exposure inhibited the expression of ACE2 protein in A549 cells by upregulating the levels of miR-200c-3p. However, APC inhibited the upregulation of miR-200c-3p induced by LPS, as well as the downregulation of ACE2 protein, through the NF-κB pathway. In conclusion, although LPS can inhibit the expression of ACE2 by upregulating the levels of miR-200c-3p through the NF-κB pathway, APC inhibited this effect, thus reducing inflammation during LPS-induced ALI.

20.
ERJ Open Res ; 7(1)2021 Jan.
Article in English | MEDLINE | ID: covidwho-1143170

ABSTRACT

Critically ill #COVID19 patients display markedly increased alternative angiotensin pathway activity compared to healthy controls, reflected by increased blood ACE2 levels as well as decreased angiotensin-II and enhanced angiotensin-1-7 formation https://bit.ly/2MU1z4z.

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