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1.
Front Biosci (Landmark Ed) ; 27(2): 48, 2022 02 11.
Article in English | MEDLINE | ID: covidwho-1772157

ABSTRACT

BACKGROUND: Thymosin-α1 has been implicated into the treatment of novel respiratory virus Coronavirus Disease 2019 (COVID-19), but the underlying mechanisms are still disputable. AIM: Herein we aimed to reveal a previously unrecognized mechanism that thymosin-α1 prevents COVID-19 by binding with angiotensin-converting enzyme (ACE), which was inspired from the tool of network pharmacology. METHODS: KEGG pathway enrichment of thymosin-α1 treating COVID-19 was analyzed by Database of Functional Annotation Bioinformatics Microarray Analysis, then core targets were validated by ligand binding kinetics assay and fluorometric detection of ACE and ACE2 enzymatic activity. The production of angiotensin I, angiotensin II, angiotensin (1-7) and angiotensin (1-9) were detected by enzyme linked immunosorbent assay. RESULTS: We found that thymosin-α1 impaired the expressions of angiotensin-converting enzyme 2 and angiotensin (1-7) of human lung epithelial cells in a dose-dependent way (p < 0.001). In contrast, thymosin-α1 had no impact on their ACE and angiotensin (1-9) expressions but significantly inhibited the enzymatic activity of ACE (p > 0.05). CONCLUSION: The bioinformatic findings of network pharmacology and the corresponding pharmacological validations have revealed that thymosin-α1 treatment could decrease ACE2 expression in human lung epithelial cells, which strengthens the potential clinical applications of thymosin-α1 to prevent severe acute respiratory syndrome coronavirus 2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/drug therapy , Humans , SARS-CoV-2 , Thymalfasin/pharmacology
2.
Int J Mol Sci ; 23(3)2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1745038

ABSTRACT

This review article is focused on antihypertensive drugs, namely angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), and their immunomodulatory properties reported in hypertensive patients as well as in experimental settings involving studies on animal models and cell lines. The immune regulatory action of ACEI and ARB is mainly connected with the inhibition of proinflammatory cytokine secretion, diminished expression of adhesion molecules, and normalization of CRP concentration in the blood plasma. The topic has significant importance in future medical practice in the therapy of patients with comorbidities with underlying chronic inflammatory responses. Thus, this additional effect of immune regulatory action of ACEI and ARB may also benefit the treatment of patients with metabolic syndrome, allergies, or autoimmune disorders.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Immunomodulation/drug effects , Animals , Antihypertensive Agents/pharmacology , COVID-19 , Humans
4.
Life Sci ; 293: 120324, 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1616648

ABSTRACT

AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.


Subject(s)
Alveolar Epithelial Cells/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Renin-Angiotensin System/physiology , Serine Endopeptidases/metabolism , Adult , Age Factors , Aged , Alveolar Epithelial Cells/chemistry , Alveolar Epithelial Cells/drug effects , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Female , Humans , Lung/chemistry , Lung/drug effects , Lung/metabolism , Male , Middle Aged , Peptide Fragments/metabolism , Renin-Angiotensin System/drug effects , Retrospective Studies , Serine Endopeptidases/analysis , Smoking/metabolism , Smoking/pathology
5.
Sci Rep ; 11(1): 23670, 2021 12 08.
Article in English | MEDLINE | ID: covidwho-1560986

ABSTRACT

Among cases of SARS-CoV-2 infections that result in serious conditions or death, many have pre-existing conditions such as hypertension and are on renin-angiotensin-aldosterone system (RAAS) inhibitors. The angiotensin-converting-enzyme-2 (ACE2), a key protein of the RAAS pathway, also mediates cellular entry of SARS-CoV-2. RAAS inhibitors might affect the expression levels of ace2, which could impact patient susceptibility to SARS-CoV-2. However, multi-organ-specific information is currently lacking and no species other than rodents have been examined. To address this knowledge gap, we treated adult zebrafish with the RAAS inhibitors aliskiren, olmesartan, and captopril for 7 consecutive days and performed qRT-PCR analysis of major RAAS pathway genes in the brain, gill, heart, intestine, kidney, and liver. Both olmesartan and captopril significantly increased ace2 expression in the heart, gill, and kidney. Olmesartan also increased ace2 expression in the intestine. Conversely, aliskiren significantly decreased ace2 expression in the heart. Discontinuation of compound treatments for 7 days did not return ace2 expression to baseline levels. While potential risks or benefits of antihypertensive RAAS inhibitors to SARS-CoV-2 infections in humans remain uncertain, this study provides new insights regarding the impact of RAAS inhibitors on organ-specific ace2 expression in another vertebrate model, thereby providing comparative data and laying scientific groundwork for future clinical decisions of RAAS inhibitor use in the context of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Down-Regulation/drug effects , Up-Regulation/drug effects , Zebrafish/metabolism , Amides/pharmacology , Angiotensin-Converting Enzyme 2/genetics , Animals , Brain/drug effects , Brain/metabolism , COVID-19/pathology , COVID-19/virology , Fumarates/pharmacology , Gills/drug effects , Gills/metabolism , Humans , Imidazoles/pharmacology , Liver/drug effects , Liver/metabolism , Models, Animal , SARS-CoV-2/isolation & purification , Tetrazoles/pharmacology
6.
J Renin Angiotensin Aldosterone Syst ; 2021: 6824259, 2021.
Article in English | MEDLINE | ID: covidwho-1546597

ABSTRACT

Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and, consequently, has high hospitalization and mortality rates. Moreover, people who contract COVID-19 present systemic inflammatory spillover. It is now known that COVID-19 pathogenesis is linked to the renin-angiotensin system (RAS). COVID-19 invades host cells via the angiotensin-converting enzyme 2 (ACE2) receptor-as such, an individual's susceptibility to COVID-19 increases alongside the upregulation of this receptor. COVID-19 has also been associated with interstitial pulmonary fibrosis, which leads to acute respiratory distress, cardiomyopathy, and shock. These outcomes are thought to result from imbalances in angiotensin (Ang) II and Ang-(1-7)/alamandine activity. ACE2, Ang-(1-7), and alamandine have potent anti-inflammatory properties, and some SARS-CoV-2 patients exhibit high levels of ACE2 and Ang-(1-7). This phenomenon could indicate a failing physiological response to prevent or reduce the severity of inflammation-mediated pulmonary injuries. Alamandine, which is another protective component of the RAS, has several health benefits owing to its antithrombogenic, anti-inflammatory, and antifibrotic characteristics. Alamandine alleviates pulmonary fibrosis via the Mas-related G protein-coupled receptor D (MrgD). Thus, a better understanding of this pathway could uncover novel pharmacological strategies for altering proinflammatory environments within the body. Following such strategies could inhibit fibrosis after SARS-CoV-2 infection and, consequently, prevent COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Oligopeptides/therapeutic use , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , COVID-19/metabolism , Humans , Peptide Fragments/metabolism , Renin-Angiotensin System/drug effects
7.
BMJ ; 375: n2938, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1537932

Subject(s)
Adrenergic beta-Antagonists/adverse effects , Blood Pressure/drug effects , Diabetes Mellitus/prevention & control , Hypertension/drug therapy , Thiazides/adverse effects , Adrenergic beta-Antagonists/therapeutic use , Aminobutyrates/pharmacology , Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Biphenyl Compounds/pharmacology , Biphenyl Compounds/therapeutic use , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/therapy , COVID-19/virology , Calcium Channel Blockers/adverse effects , Calcium Channel Blockers/therapeutic use , Cats , Diabetes Mellitus/etiology , Diabetes Mellitus, Type 2/drug therapy , Dogs , Drug Combinations , Gastric Inhibitory Polypeptide/adverse effects , Gastric Inhibitory Polypeptide/pharmacology , Gastric Inhibitory Polypeptide/therapeutic use , Heart Sounds/physiology , History, 20th Century , Humans , Hypertension/complications , Immunization, Passive/methods , Immunization, Passive/statistics & numerical data , Incretins/adverse effects , Incretins/pharmacology , Incretins/therapeutic use , Insulin Glargine/adverse effects , Insulin Glargine/history , Insulin Glargine/pharmacology , Insulin Glargine/therapeutic use , Meta-Analysis as Topic , Randomized Controlled Trials as Topic , SARS-CoV-2/genetics , Thiazides/therapeutic use , Valsartan/pharmacology , Valsartan/therapeutic use
8.
Curr Drug Targets ; 23(4): 364-372, 2022.
Article in English | MEDLINE | ID: covidwho-1502211

ABSTRACT

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been reported as a portal for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Consequently, scientific strategies to combat coronavirus disease of 2019 (COVID-19) were targeted to arrest SARS-CoV-2 invasion by blocking ACE2. While blocking ACE2 appears a beneficial approach to treat COVID-19, clinical concerns have been raised primarily due to the various intrinsic roles of ACE2 in neurological functions. Selective reports indicate that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) upregulate ACE2 levels. ACE2 metabolizes angiotensin II and several peptides, including apelin-13, neurotensin, kinetensin, dynorphin, (des-Arg9) bradykinin, and (Lys-des-Arg9)-bradykinin, which may elicit neuroprotective effects. Since ARBs and ACEIs upregulate ACE2, it may be hypothesized that patients with hypertension receiving ARBs and ACEIs may have higher expression of ACE2 and thus be at a greater risk of severe disease from the SARS-CoV-2 infections. However, recent clinical reports indicate the beneficial role of ARBs/ACEIs in reducing COVID-19 severity. Together, this warrants a further study of the effects of ACE2 blockades in hypertensive patients medicated with ARBs/ACEIs, and their consequential impact on neuronal health. However, the associations between their blockade and any neuroinflammation also warrant further research. OBJECTIVE: This review collates mechanistic insights into the dichotomous roles of ACE2 in SARSCoV- 2 invasion and neurometabolic functions and the possible impact of ACE2 blockade on neuroinflammation. CONCLUSION: It has been concluded that ACE2 blockade imposes neuroinflammation.


Subject(s)
COVID-19 , Hypertension , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Bradykinin/pharmacology , Bradykinin/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Humans , Hypertension/drug therapy , Renin-Angiotensin System , SARS-CoV-2
10.
Int J Mol Sci ; 22(21)2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1488613

ABSTRACT

The renin-angiotensin system (RAS) is a key regulator of blood pressure and hypertension. Angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme I (ACE) are two main components of the RAS that play a major role in blood pressure homeostasis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a receptor to enter cells. Despite some controversies, numerous studies have reported a significant association between the use of ACE inhibitors and reduced risk of COVID-19. In our previous studies, we produced and identified peptide sequences present in whey hydrolysates exhibiting high ACE inhibitory activity. Therefore, the aim of this work is to obtain an improved understanding of the function of these natural peptides as RAS inhibitors and investigate their potential therapeutic role in the COVID-19 pandemic. The molecular interactions between peptides IPP, LIVTQ, IIAE, LVYPFP, and human ACE2 were assessed by employing a molecular docking approach. The results show that natural whey-derived peptides have a dual inhibitory action against both ACE and ACE2. This dual activity distinguishes these ACE inhibitory peptides from synthetic drugs, such as Captopril and Lisinopril which were not shown to inhibit ACE2 activity, and may represent a potential strategy in the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Peptides/chemistry , Peptides/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Peptides/metabolism , Peptidyl-Dipeptidase A/chemistry , Renin-Angiotensin System/drug effects , Whey Proteins/chemistry
11.
J Dent Res ; 101(1): 5-10, 2022 01.
Article in English | MEDLINE | ID: covidwho-1484182

ABSTRACT

The emergence of the COVID-19 viral pandemic has generated a renewed interest in pharmacologic agents that target the renin angiotensin system (RAS). Angiotensin-converting enzyme 1 (ACE1) inhibitors decrease the synthesis of angiotensin II (Ang II) from its precursor angiotensin I and inhibit the breakdown of bradykinin, while Ang II receptor blockers antagonize the action of Ang II at the receptor level downstream. The actions of both classes of drugs lead to vasodilation, a blunting of sympathetic drive and a reduction in aldosterone release, all beneficial effects in hypertension and congestive heart failure. ACE2 cleaves the vasoconstrictor Ang II to produce the anti-inflammatory cytoprotective angiotensin 1-7 (Ang 1-7) peptide, which functions through the G protein-coupled receptor MAS to counteract the pathophysiologic effects induced by Ang II via its receptors, including vasoconstriction, inflammation, hypercoagulation, and fibrosis. SARS-CoV-2 enters human cells by binding ACE2 on the cell surface, decreases ACE2 activity, competes for ACE2 receptor-binding sites, and shifts the RAS toward an overexpression of Ang II, accounting for many of the deleterious effects of the virus. Thus, there is great interest in developing recombinant ACE2 as a therapeutic for prevention or treatment of COVID-19. Notably, ACE2 is highly expressed in the oral cavity, and saliva and dorsum of the tongue are major reservoirs of SARS-CoV-2. Cost-effective methods to debulk the virus in the oral cavity may aid in the prevention of viral spread. Here we review the pharmacology of targeted small molecule inhibitors of the RAS and discuss novel approaches to employing ACE2 as a therapeutic for COVID-19.


Subject(s)
COVID-19 , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Humans , Renin-Angiotensin System , SARS-CoV-2
12.
Cells ; 10(10)2021 10 14.
Article in English | MEDLINE | ID: covidwho-1470799

ABSTRACT

The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.


Subject(s)
COVID-19/blood , COVID-19/metabolism , Renin-Angiotensin System , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Blood Pressure/drug effects , Humans , Peptidyl-Dipeptidase A/metabolism , Renin/pharmacology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry
13.
Front Immunol ; 12: 728896, 2021.
Article in English | MEDLINE | ID: covidwho-1456291

ABSTRACT

A purified spike (S) glycoprotein of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) coronavirus was used to study its effects on THP-1 macrophages, peripheral blood mononuclear cells (PBMCs), and HUVEC cells. The S protein mediates the entry of SARS-CoV-2 into cells through binding to the angiotensin-converting enzyme 2 (ACE2) receptors. We measured the viability, intracellular cytokine release, oxidative stress, proinflammatory markers, and THP-1-like macrophage polarization. We observed an increase in apoptosis, ROS generation, MCP-1, and intracellular calcium expression in the THP-1 macrophages. Stimulation with the S protein polarizes the THP-1 macrophages towards proinflammatory futures with an increase in the TNFα and MHC-II M1-like phenotype markers. Treating the cells with an ACE inhibitor, perindopril, at 100 µM reduced apoptosis, ROS, and MHC-II expression induced by S protein. We analyzed the sensitivity of the HUVEC cells after the exposure to a conditioned media (CM) of THP-1 macrophages stimulated with the S protein. The CM induced endothelial cell apoptosis and MCP-1 expression. Treatment with perindopril reduced these effects. However, the direct stimulation of the HUVEC cells with the S protein, slightly increased HIF1α and MCP-1 expression, which was significantly increased by the ACE inhibitor treatment. The S protein stimulation induced ROS generation and changed the mitogenic responses of the PBMCs through the upregulation of TNFα and interleukin (IL)-17 cytokine expression. These effects were reduced by the perindopril (100 µM) treatment. Proteomic analysis of the S protein stimulated THP-1 macrophages with or without perindopril (100 µM) exposed more than 400 differentially regulated proteins. Our results provide a mechanistic analysis suggesting that the blood and vascular components could be activated directly through S protein systemically present in the circulation and that the activation of the local renin angiotensin system may be partially involved in this process. Graphical: Suggested pathways that might be involved at least in part in S protein inducing activation of inflammatory markers (red narrow) and angiotensin-converting enzyme inhibitor (ACEi) modulation of this process (green narrow).


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Apoptosis/drug effects , COVID-19/immunology , Macrophages/immunology , Oxidative Stress/drug effects , Perindopril/pharmacology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/virology , Cell Line , Humans , Macrophages/drug effects , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pyroptosis/drug effects , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
14.
Cardiovasc Hematol Disord Drug Targets ; 20(3): 181-184, 2020.
Article in English | MEDLINE | ID: covidwho-1435708

ABSTRACT

Nowadays Coronavirus Disease 2019 (Covid-19) is increasing mortality all over the world mercilessly. We are learning almost every day about its new symptoms and that it mutates quickly. This disease has tied us up and made us desperate. The death rate from this disease has increased in patients who had pre-existing medical conditions, especially cardiovascular ones, by eliminating the angiotensin-converting enzyme (ACE)-2 receptor in the lungs. Also, ACE1 and angiotensin receptor blockers (ARB) may stimulate ACE2 expression and worse the prognosis. Intravenous infusions of ACEIs and ARBs in experimental animals increase the number of ACE2 receptors. Therefore, it may be one of the reasons that COVID-19 infects the cells of patients treating hypertension. However, most of the congress of cardiology do not recommend to discontinue these anti-hypertensive drugs. Therefore, this brief report evaluates Covid-19 in the view of cardiovascular diseases taking into account current reports and suggests some possible solutions to keep the virus under control.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Age Factors , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antihypertensive Agents/therapeutic use , COVID-19/complications , COVID-19/mortality , Cardiovascular Diseases/metabolism , Humans , Hypertension/drug therapy , Pandemics , SARS-CoV-2 , Severity of Illness Index , Thromboembolism/etiology , Thromboembolism/physiopathology
16.
Front Cell Infect Microbiol ; 11: 639177, 2021.
Article in English | MEDLINE | ID: covidwho-1389152

ABSTRACT

Several comorbidities, including hypertension, have been associated with an increased risk of developing severe disease during SARS-CoV-2 infection. Angiotensin II receptor blockers (ARBs) are currently some of the most widely-used drugs to control blood pressure by acting on the angiotensin II type 1 receptor (AT1R). ARBs have been reported to trigger the modulation of the angiotensin I converting enzyme 2 (ACE2), the receptor used by the virus to penetrate susceptible cells, raising concern that such treatments may promote virus capture and increase their viral load in patients receiving ARBs therapy. In this in vitro study, we reviewed the effect of ARBs on ACE2 and AT1R expression and investigated whether treatment of permissive ACE2+/AT1R+ Vero E6 cells with ARBs alters SARS-CoV-2 replication in vitro in an angiotensin II-free system. After treating the cells with the ARBs, we observed an approximate 50% relative increase in SARS-CoV-2 production in infected Vero E6 cells that correlates with the ARBs-induced up-regulation of ACE2 expression. From this data, we believe that the use of ARBs in hypertensive patients infected by SARS-CoV-2 should be carefully evaluated.


Subject(s)
Angiotensin Receptor Antagonists , COVID-19 , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antihypertensive Agents/pharmacology , Humans , Renin-Angiotensin System , SARS-CoV-2
18.
J Mol Model ; 27(7): 206, 2021 Jun 24.
Article in English | MEDLINE | ID: covidwho-1384472

ABSTRACT

The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhizic Acid/pharmacology , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/chemistry , Animals , Antiviral Agents/chemistry , Binding Sites , COVID-19/enzymology , COVID-19/virology , Drug Discovery , Drug Repositioning , Glycyrrhizic Acid/analogs & derivatives , Glycyrrhizic Acid/chemistry , Host-Pathogen Interactions , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Structure-Activity Relationship
20.
Pharmacol Res ; 173: 105848, 2021 11.
Article in English | MEDLINE | ID: covidwho-1373221

ABSTRACT

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Health Equity/trends , Pharmacology, Clinical/trends , Randomized Controlled Trials as Topic/methods , Sex Characteristics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/blood , COVID-19/drug therapy , COVID-19/immunology , Gonadal Steroid Hormones/antagonists & inhibitors , Gonadal Steroid Hormones/blood , Humans , Pharmacology, Clinical/methods , Precision Medicine/methods , Precision Medicine/trends
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