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1.
Crit Care ; 26(1): 171, 2022 06 09.
Article in English | MEDLINE | ID: covidwho-1951302

ABSTRACT

BACKGROUND: SARS-CoV-2 infection leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Both clinical data and animal experiments suggest that the renin-angiotensin system (RAS) is involved in the pathogenesis of SARS-CoV-2-induced ALI. Angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2 and a crucial negative regulator of RAS. Recombinant ACE2 protein (rACE2) has been demonstrated to play protective role against SARS-CoV and avian influenza-induced ALI, and more relevant, rACE2 inhibits SARS-CoV-2 proliferation in vitro. However, whether rACE2 protects against SARS-CoV-2-induced ALI in animal models and the underlying mechanisms have yet to be elucidated. METHODS AND RESULTS: Here, we demonstrated that the SARS-CoV-2 spike receptor-binding domain (RBD) protein aggravated lipopolysaccharide (LPS)-induced ALI in mice. SARS-CoV-2 spike RBD protein directly binds and downregulated ACE2, leading to an elevation in angiotensin (Ang) II. AngII further increased the NOX1/2 through AT1R, subsequently causing oxidative stress and uncontrolled inflammation and eventually resulting in ALI/ARDS. Importantly, rACE2 remarkably reversed SARS-CoV-2 spike RBD protein-induced ALI by directly binding SARS-CoV-2 spike RBD protein, cleaving AngI or cleaving AngII. CONCLUSION: This study is the first to prove that rACE2 plays a protective role against SARS-CoV-2 spike RBD protein-aggravated LPS-induced ALI in an animal model and illustrate the mechanism by which the ACE2-AngII-AT1R-NOX1/2 axis might contribute to SARS-CoV-2-induced ALI.


Subject(s)
Acute Lung Injury , Angiotensin-Converting Enzyme 2 , COVID-19 , Respiratory Distress Syndrome , Acute Lung Injury/prevention & control , Acute Lung Injury/virology , Angiotensin II , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , COVID-19/complications , Humans , Lipopolysaccharides , Mice , Recombinant Proteins/therapeutic use , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
2.
J Am Soc Nephrol ; 33(7): 1293-1307, 2022 07.
Article in English | MEDLINE | ID: covidwho-1799028

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as a main receptor to enter target cells. The goal of this study was to demonstrate the preclinical efficacy of a novel soluble ACE2 protein with increased duration of action and binding capacity in a lethal mouse model of COVID-19. METHODS: A human soluble ACE2 variant fused with an albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide (DDC) to improve binding capacity to SARS-CoV-2. This novel soluble ACE2 protein (ACE2-1-618-DDC-ABD) was then administered intranasally and intraperitoneally to mice before intranasal inoculation of SARS-CoV-2 and then for two additional days post viral inoculation. RESULTS: Untreated animals became severely ill, and all had to be humanely euthanized by day 6 or 7 and had pulmonary alveolar hemorrhage with mononuclear infiltrates. In contrast, all but one mouse infected with a lethal dose of SARS-CoV-2 that received ACE2-1-618-DDC-ABD survived. In the animals inoculated with SARS-CoV-2 that were untreated, viral titers were high in the lungs and brain, but viral titers were absent in the kidneys. Some untreated animals, however, had variable degrees of kidney proximal tubular injury as shown by attenuation of the proximal tubular brush border and increased NGAL and TUNEL staining. Viral titers in the lung and brain were reduced or nondetectable in mice that received ACE2-1-618-DDC-ABD, and the animals developed only moderate disease as assessed by a near-normal clinical score, minimal weight loss, and improved lung and kidney injury. CONCLUSIONS: This study demonstrates the preclinical efficacy of a novel soluble ACE2 protein, termed ACE2-1-618-DDC-ABD, in a lethal mouse model of SARS-CoV-2 infection that develops severe lung injury and variable degrees of moderate kidney proximal tubular injury.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , COVID-19/therapy , Kidney/virology , Lung/virology , Mice , SARS-CoV-2
3.
Am J Physiol Regul Integr Comp Physiol ; 321(6): R833-R843, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1541942

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound protein containing 805 amino acids. ACE2 shows approximately 42% sequence similarity to somatic ACE but has different biochemical activities. The key role of ACE2 is to catalyze the vasoconstrictor peptide angiotensin (ANG) II to Ang-(1-7), thus regulating the two major counterbalancing pathways of the renin-angiotensin system (RAS). In this way, ACE2 plays a protective role in end-organ damage by protecting tissues from the proinflammatory actions of ANG II. The circulating RAS is activated in normal pregnancy and is essential for maintaining fluid and electrolyte homeostasis and blood pressure. Renin-angiotensin systems are also found in the conceptus. In this review, we summarize the current knowledge on the regulation and function of circulating and uteroplacental ACE2 in uncomplicated and complicated pregnancies, including those affected by preeclampsia and fetal growth restriction. Since ACE2 is the receptor for SARS-CoV-2, and COVID-19 in pregnancy is associated with more severe disease and increased risk of abnormal pregnancy outcomes, we also discuss the role of ACE2 in mediating some of these adverse consequences. We propose that dysregulation of ACE2 plays a critical role in the development of preeclampsia, fetal growth restriction, and COVID-19-associated pregnancy pathologies and suggest that human recombinant soluble ACE2 could be a novel therapeutic to treat and/or prevent these pregnancy complications.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Placenta/enzymology , Pregnancy Complications/enzymology , Renin-Angiotensin System , Uterus/enzymology , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , Blood Pressure , COVID-19/enzymology , COVID-19/physiopathology , COVID-19/virology , Female , Fetal Growth Retardation/enzymology , Fetal Growth Retardation/physiopathology , Humans , Inflammation Mediators/metabolism , Placenta/physiopathology , Pre-Eclampsia/enzymology , Pre-Eclampsia/physiopathology , Pregnancy , Pregnancy Complications/drug therapy , Pregnancy Complications/physiopathology , Pregnancy Complications, Infectious/enzymology , Pregnancy Complications, Infectious/physiopathology , Pregnancy Complications, Infectious/virology , SARS-CoV-2/pathogenicity , Uterus/physiopathology , Water-Electrolyte Balance
4.
Viruses ; 13(11)2021 11 08.
Article in English | MEDLINE | ID: covidwho-1512697

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells mainly by the angiotensin converting enzyme 2 (ACE2) receptor, which can recognize the spike (S) protein by its extracellular domain. Previously, recombinant soluble ACE2 (sACE2) has been clinically used as a therapeutic treatment for cardiovascular diseases. Recent data demonstrated that sACE2 can also be exploited as a decoy to effectively inhibit the cell entry of SARS-CoV-2, through blocking SARS-CoV-2 binding to membrane-anchored ACE2. In this study, we summarized the current findings on the optimized sACE2-based strategies as a therapeutic agent, including Fc fusion to prolong the half-life of sACE2, deep mutagenesis to create high-affinity decoys for SARS-CoV-2, or designing the truncated functional fragments to enhance its safety, among others. Considering that COVID-19 patients are often accompanied by manifestations of cardiovascular complications, we think that administration of sACE2 in COVID-19 patients may be a promising therapeutic strategy to simultaneously treat both cardiovascular diseases and SARS-CoV-2 infection. This review would provide insights for the development of novel therapeutic agents against the COVID-19 pandemic.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Cardiovascular Diseases/drug therapy , Recombinant Fusion Proteins/therapeutic use , SARS-CoV-2 , Animals , COVID-19/complications , Cardiovascular Diseases/complications , Humans , Peptidyl-Dipeptidase A , Protein Binding , Protein Engineering , Receptors, Virus/metabolism , Receptors, Virus/therapeutic use , Spike Glycoprotein, Coronavirus
5.
Antiviral Res ; 196: 105197, 2021 12.
Article in English | MEDLINE | ID: covidwho-1509565

ABSTRACT

SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemical synthesis , COVID-19/drug therapy , Immunoglobulin G , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/therapeutic use , Antiviral Agents/therapeutic use , Humans , Protein Binding , SARS-CoV-2/drug effects
6.
Acta Physiol (Oxf) ; 231(1): e13513, 2021 01.
Article in English | MEDLINE | ID: covidwho-1388186

ABSTRACT

The renin angiotensin system (RAS) plays an important role in the pathogenesis of variety of diseases. Targeting the formation and action of angiotensin II (Ang II), the main RAS peptide, has been the key therapeutic target for last three decades. ACE-related carboxypeptidase (ACE2), a monocarboxypeptidase that had been discovered 20 years ago, is one of the catalytically most potent enzymes known to degrade Ang II to Ang-(1-7), a peptide that is increasingly accepted to have organ-protective properties that oppose and counterbalance those of Ang II. In addition to its role as a RAS enzyme ACE2 is the main receptor for SARS-CoV-2. In this review, we discuss various strategies that have been used to achieve amplification of ACE2 activity including the potential therapeutic potential of soluble recombinant ACE2 protein and novel shorter ACE2 variants.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/therapy , Genetic Therapy , Receptors, Virus , SARS-CoV-2/pathogenicity , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , COVID-19/enzymology , COVID-19/genetics , COVID-19/virology , Enzyme Activation , Enzyme Activators/therapeutic use , Gene Amplification , Host-Pathogen Interactions , Humans , Receptors, Virus/genetics , Receptors, Virus/metabolism , Receptors, Virus/therapeutic use , Recombinant Proteins/therapeutic use
7.
Med Hypotheses ; 144: 109976, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1386300

ABSTRACT

Several attempts to control the dreadfulness of SARS-CoV-2 are still underway. Based on the literature evidences we have speculated a prospective contemporary remedy, which was categorized into Specificity, Remedy, and a Conveyor. In which, pros and cons were discussed and inferred the possible alternatives. (a) Specificity: Implicit to express the ACE2 receptors in conveyor cells to deceive SARS-CoV-2 frompreponetargets. (b) Remedy: As depletion of pulmonary surfactants causes strong acute respiratory distress syndrome, we propose an entity of a cost-effective artificialsurfactantsystem as a remedy to pulmonary complications. (c) Conveyor: We propose red blood cells (RBCs) as a conveyor with embedded artificial surfactant and protruding ACE2 receptors for the target-specific delivery. Overall we postulate focused insights by employing a combinational contemporary strategy to steer towards a prospective direction on combating SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/therapeutic use , COVID-19/virology , Erythrocytes , Pulmonary Surfactants/therapeutic use , Receptors, Virus/therapeutic use , SARS-CoV-2/physiology , Viral Tropism , Angiotensin-Converting Enzyme 2/administration & dosage , COVID-19/complications , COVID-19/prevention & control , Drug Costs , Drug Delivery Systems , Humans , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/virology , Pulmonary Surfactants/administration & dosage , Pulmonary Surfactants/chemical synthesis , Pulmonary Surfactants/economics , Receptors, Virus/administration & dosage , Respiratory Distress Syndrome/prevention & control
8.
Int J Mol Sci ; 22(17)2021 Aug 25.
Article in English | MEDLINE | ID: covidwho-1376841

ABSTRACT

In recent years, enzymes have risen as promising therapeutic tools for different pathologies, from metabolic deficiencies, such as fibrosis conditions, ocular pathologies or joint problems, to cancer or cardiovascular diseases. Treatments based on the catalytic activity of enzymes are able to convert a wide range of target molecules to restore the correct physiological metabolism. These treatments present several advantages compared to established therapeutic approaches thanks to their affinity and specificity properties. However, enzymes present some challenges, such as short in vivo half-life, lack of targeted action and, in particular, patient immune system reaction against the enzyme. For this reason, it is important to monitor serum immune response during treatment. This can be achieved by conventional techniques (ELISA) but also by new promising tools such as microarrays. These assays have gained popularity due to their high-throughput analysis capacity, their simplicity, and their potential to monitor the immune response of patients during enzyme therapies. In this growing field, research is still ongoing to solve current health problems such as COVID-19. Currently, promising therapeutic alternatives using the angiotensin-converting enzyme 2 (ACE2) are being studied to treat COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/therapeutic use , COVID-19/drug therapy , Enzyme Therapy/methods , Recombinant Proteins/therapeutic use , Angiotensin-Converting Enzyme 2/pharmacology , Clinical Trials, Phase II as Topic , Drug Compounding/methods , Enzyme Stability , Enzyme Therapy/history , Enzyme Therapy/trends , Half-Life , History, 20th Century , History, 21st Century , Humans , Recombinant Proteins/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Treatment Outcome , Virus Internalization/drug effects
9.
Pharmacol Rep ; 73(6): 1539-1550, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1281363

ABSTRACT

Angiotensin-converting enzyme (ACE) and its homologue, ACE2, are commonly allied with hypertension, renin-angiotensin-aldosterone system pathway, and other cardiovascular system disorders. The recent pandemic of COVID-19 has attracted the attention of numerous researchers on ACE2 receptors, where the causative viral particle, SARS-CoV-2, is established to exploit these receptors for permitting their entry into the human cells. Therefore, studies on the molecular origin and pathophysiology of the cell response in correlation to the role of ACE2 receptors to these viruses are bringing novel theories. The varying level of manifestation and importance of ACE proteins, underlying irregularities and disorders, intake of specific medications, and persistence of assured genomic variants at the ACE genes are potential questions raising nowadays while observing the marked alteration in response to the SARS-CoV-2-infected patients. Therefore, the present review has focused on several raised opinions associated with the role of the ACE2 receptor and its impact on COVID-19 pathogenesis.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/pharmacology , COVID-19/drug therapy , SARS-CoV-2/pathogenicity , Acute Lung Injury , Angiotensin-Converting Enzyme 2/deficiency , Angiotensin-Converting Enzyme 2/therapeutic use , Humans , Hypertension/drug therapy , Spike Glycoprotein, Coronavirus/metabolism
10.
Naunyn Schmiedebergs Arch Pharmacol ; 394(7): 1589-1593, 2021 07.
Article in English | MEDLINE | ID: covidwho-1274804

ABSTRACT

In March 2019, the global COVID-19 pandemic caused by the novel SARS-CoV-2 coronavirus began. The first cases of SARS-CoV-2 infection occurred in November 19 in Wuhan, China. Preventive measures taken have not prevented the rapid spread of the virus to countries around the world. To date, there are approximately 3 million deaths, and a massive worldwide vaccination campaign has recently begun. SARS-CoV-2 uses the ACE-2 protein as an intracellular carrier. ACE-2 is a key component of the renin-angiotensin system (RAS), a key regulator of cardiovascular function. Considering the key role of ACE-2 in COVID-19 infection, both as an entry receptor and as a protective role, especially for the respiratory tract, and considering the variations of ACE-2 during the phases of viral infection, it is clear the important role that pharmacological regulation of RAS and ACE-2 may take. In this article, we describe the importance of ACE-2 in COVID-19 infection, the pharmacological aspects of a modulation with RAS-modifying agents, new therapeutic strategies, trying to provide a deep understanding and explanation of the complex mechanisms underlying the relationship between the virus and ACE-2, providing opinions and personal hypotheses on the best strategies of therapeutic intervention.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Renin-Angiotensin System/drug effects , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Animals , COVID-19/enzymology , COVID-19/virology , Host-Pathogen Interactions , Humans , Recombinant Proteins/therapeutic use , SARS-CoV-2/pathogenicity
11.
Cardiovasc Toxicol ; 21(6): 498-503, 2021 06.
Article in English | MEDLINE | ID: covidwho-1173998

ABSTRACT

In March 2019 began the global pandemic COVID-19 caused by the new Coronavirus SARS-CoV-2. The first cases of SARS-CoV-2 infection occurred in November-19 in Wuhan, China. The preventive measures taken did not prevent the rapid spread of the virus to all countries around the world. To date, there are about 2.54 million deaths, effective vaccines are in clinical trials. SARS-CoV-2 uses the ACE-2 protein as an intracellular gateway. ACE-2 is a key component of the Renin Angiotensin (RAS) system, a key regulator of cardiovascular function. Considering the key role of ACE-2 in COVID-19 infection, both as an entry receptor and as a protective role, especially for the respiratory tract, and considering the variations of ACE-2 and ACE during the stages of viral infection, it is clear the important role that the pharmacological regulation of RAS and ACE-2 can assume. This biological knowledge suggests different pharmacological approaches to treat COVID-19 by modulating RAS, ACE-2 and the ACE/ACE2 balance that we describe in this article.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lung/drug effects , Receptors, Virus/metabolism , Renin-Angiotensin System/drug effects , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Antiviral Agents/adverse effects , COVID-19/enzymology , COVID-19/virology , Host-Pathogen Interactions , Humans , Lung/enzymology , Lung/virology , Recombinant Proteins/therapeutic use , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Virus Internalization
13.
Sci Adv ; 7(8)2021 02.
Article in English | MEDLINE | ID: covidwho-1088182

ABSTRACT

The spike S of SARS-CoV-2 recognizes ACE2 on the host cell membrane to initiate entry. Soluble decoy receptors, in which the ACE2 ectodomain is engineered to block S with high affinity, potently neutralize infection and, because of close similarity with the natural receptor, hold out the promise of being broadly active against virus variants without opportunity for escape. Here, we directly test this hypothesis. We find that an engineered decoy receptor, sACE22v2.4, tightly binds S of SARS-associated viruses from humans and bats, despite the ACE2-binding surface being a region of high diversity. Saturation mutagenesis of the receptor-binding domain followed by in vitro selection, with wild-type ACE2 and the engineered decoy competing for binding sites, failed to find S mutants that discriminate in favor of the wild-type receptor. We conclude that resistance to engineered decoys will be rare and that decoys may be active against future outbreaks of SARS-associated betacoronaviruses.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , COVID-19 , Protein Engineering , SARS-CoV-2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , COVID-19/drug therapy , Cell Line , Chiroptera , Humans , Mutagenesis , Protein Domains , SARS-CoV-2/genetics , SARS-CoV-2/metabolism
14.
Nat Struct Mol Biol ; 28(2): 202-209, 2021 02.
Article in English | MEDLINE | ID: covidwho-1065920

ABSTRACT

Effective intervention strategies are urgently needed to control the COVID-19 pandemic. Human angiotensin-converting enzyme 2 (ACE2) is a membrane-bound carboxypeptidase that forms a dimer and serves as the cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 is also a key negative regulator of the renin-angiotensin system that modulates vascular functions. We report here the properties of a trimeric ACE2 ectodomain variant, engineered using a structure-based approach. The trimeric ACE2 variant has a binding affinity of ~60 pM for the spike protein of SARS­CoV­2 (compared with 77 nM for monomeric ACE2 and 12-22 nM for dimeric ACE2 constructs), and its peptidase activity and the ability to block activation of angiotensin II receptor type 1 in the renin-angiotensin system are preserved. Moreover, the engineered ACE2 potently inhibits SARS­CoV­2 infection in cell culture. These results suggest that engineered, trimeric ACE2 may be a promising anti-SARS-CoV-2 agent for treating COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/therapeutic use , Antiviral Agents/therapeutic use , Cryoelectron Microscopy , Humans , Models, Molecular , Protein Engineering , Protein Multimerization , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/therapeutic use , SARS-CoV-2/physiology
15.
Am J Physiol Cell Physiol ; 320(3): C279-C281, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1050414

ABSTRACT

Soluble angiotensin-converting enzyme 2 (sACE2) could be a therapeutic option to treat coronavirus disease 2019 (COVID-19) infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes ACE2 receptors on cell surfaces to gain intracellular entry, making them an ideal target for therapy. High-affinity variants of sACE2, engineered using high-throughput mutagenesis, are capable of neutralizing COVID-19 infection as decoy receptors. These variants compete with native ACE2 present on cells by binding with spike (S) protein of SARS-CoV-2, making native ACE2 on cell surfaces available to convert angiotensin II to angiotensin-1,7, thus alleviating the exaggerated inflammatory response associated with COVID-19 infection. This article explores the use of sACE2 as potential therapy for COVID-19 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/therapeutic use , COVID-19/drug therapy , SARS-CoV-2 , Humans , Protein Binding , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
16.
J Neuroimmune Pharmacol ; 16(1): 59-70, 2021 03.
Article in English | MEDLINE | ID: covidwho-1018438

ABSTRACT

COVID-19 is an infectious respiratory illness caused by the virus strain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and until now, there is no effective therapy against COVID-19. Since SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) for entering into host cells, to target COVID-19 from therapeutic angle, we engineered a hexapeptide corresponding to the ACE2-interacting domain of SARS-CoV-2 (AIDS) that inhibits the association between receptor-binding domain-containing spike S1 and ACE-2. Accordingly, wild type (wt), but not mutated (m), AIDS peptide inhibited SARS-CoV-2 spike S1-induced activation of NF-κB and expression of IL-6 in human lungs cells. Interestingly, intranasal intoxication of C57/BL6 mice with recombinant SARS-CoV-2 spike S1 led to fever, increase in IL-6 in lungs, infiltration of neutrophils into the lungs, arrhythmias, and impairment in locomotor activities, mimicking some of the important symptoms of COVID-19. However, intranasal treatment with wtAIDS, but not mAIDS, peptide reduced fever, protected lungs, improved heart function, and enhanced locomotor activities in SARS-CoV-2 spike S1-intoxicated mice. Therefore, selective targeting of ACE2-to-SARS-CoV-2 interaction by wtAIDS may be beneficial for COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Fever/drug therapy , Fever/etiology , Heart Diseases/etiology , Heart Diseases/prevention & control , Inflammation/drug therapy , Inflammation/etiology , Lung Diseases/etiology , Lung Diseases/prevention & control , Peptide Fragments/therapeutic use , Administration, Intranasal , Animals , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/prevention & control , COVID-19/pathology , Female , Heart Diseases/pathology , Interleukin-6/metabolism , Lung Diseases/pathology , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Neutrophil Infiltration/drug effects , Spike Glycoprotein, Coronavirus/toxicity
17.
Molecules ; 25(23)2020 Nov 25.
Article in English | MEDLINE | ID: covidwho-945888

ABSTRACT

A serious pandemic has been caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The interaction between spike surface viral protein (Sgp) and the angiotensin-converting enzyme 2 (ACE2) cellular receptor is essential to understand the SARS-CoV-2 infectivity and pathogenicity. Currently, no drugs are available to treat the infection caused by this coronavirus and the use of antimicrobial peptides (AMPs) may be a promising alternative therapeutic strategy to control SARS-CoV-2. In this study, we investigated the in silico interaction of AMPs with viral structural proteins and host cell receptors. We screened the antimicrobial peptide database (APD3) and selected 15 peptides based on their physicochemical and antiviral properties. The interactions of AMPs with Sgp and ACE2 were performed by docking analysis. The results revealed that two amphibian AMPs, caerin 1.6 and caerin 1.10, had the highest affinity for Sgp proteins while interaction with the ACE2 receptor was reduced. The effective AMPs interacted particularly with Arg995 located in the S2 subunits of Sgp, which is key subunit that plays an essential role in viral fusion and entry into the host cell through ACE2. Given these computational findings, new potentially effective AMPs with antiviral properties for SARS-CoV-2 were identified, but they need experimental validation for their therapeutic effectiveness.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , COVID-19/drug therapy , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amphibian Proteins/chemistry , Amphibian Proteins/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/therapeutic use , Antimicrobial Cationic Peptides/chemistry , Antimicrobial Cationic Peptides/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Binding Sites/genetics , COVID-19/genetics , COVID-19/virology , Computer Simulation , Humans , Pandemics , Pore Forming Cytotoxic Proteins/chemistry , Pore Forming Cytotoxic Proteins/therapeutic use , Protein Binding/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/therapeutic use , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , Viral Structural Proteins/therapeutic use
18.
Gastroenterology ; 160(1): 39-46, 2021 01.
Article in English | MEDLINE | ID: covidwho-936157

ABSTRACT

The role of angiotensin converting enzyme 2 has expanded from regulating the renin angiotensin system to regulating intestinal amino acid homeostasis and the gut microbiome. Recently, angiotensin converting enzyme 2 was identified as a primary receptor for severe acute respiratory syndrome coronaviruses 1 and 2 being expressed in multiple tissues including the luminal surface of the gut. In this brief perspective, we examine the role of angiotensin converting enzyme 2 as the receptor for severe acute respiratory syndrome coronavirus 2 and the impact of coronavirus disease 19 infection on the gut microbiome and on the gut epithelium.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , Gastroenteritis/enzymology , Gastrointestinal Microbiome , Intestinal Mucosa/enzymology , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/microbiology , COVID-19/virology , Feces/microbiology , Feces/virology , Gastroenteritis/drug therapy , Gastroenteritis/microbiology , Gastroenteritis/virology , Gastrointestinal Microbiome/drug effects , Host-Pathogen Interactions , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/microbiology , Intestinal Mucosa/virology , Renin-Angiotensin System , SARS-CoV-2/drug effects , Virus Internalization
19.
Clin Sci (Lond) ; 134(19): 2581-2595, 2020 10 16.
Article in English | MEDLINE | ID: covidwho-872745

ABSTRACT

The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin-angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein-coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.


Subject(s)
Angiotensin-Converting Enzyme 2/therapeutic use , Animals , Disease Models, Animal , Gene Transfer Techniques , Humans , Models, Biological , Organ Specificity , Renin-Angiotensin System
20.
Immunol Cell Biol ; 99(2): 192-205, 2021 02.
Article in English | MEDLINE | ID: covidwho-735921

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has affected the daily lives of millions of people worldwide and had caused significant mortality; hence, the assessment of therapeutic options is of great interest. The leading cause of death among COVID-19 patients is acute respiratory distress syndrome caused by hyperinflammation secondary to cytokine release syndrome (CRS). Cytokines, such as tumor necrosis factor-α, interleukin-6, interferon-γ and interleukin-10, are the main mediators of CRS. Based on recent evidence, the angiotensin-converting enzyme (ACE) II is known to be the target of the COVID-19 spike protein, which enables the virus to penetrate human cells. ACE II also possesses an anti-inflammatory role in many pathologies such as cardiovascular disease, hypertension, diabetes mellitus and other conditions, which are the main risk factors of poor prognosis in COVID-19 infection. Changes in tissue ACE II levels are associated with many diseases and hyperinflammatory states, and it is assumed that elevated levels of ACE II could aggravate the course of COVID-19 infection. Therefore, the use of renin-angiotensin-aldosterone system inhibitors (RASis) in COVID-19 patients could be hypothetically considered, though sufficient evidence is not presented by the scientific community. In this work, based on the most recent pieces of evidence, the roles of RAS and RASi in immunologic interactions are addressed. Furthermore, the molecular and immunologic aspects of RASi and their potential significance in COVID-19 are discussed.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , COVID-19 , SARS-CoV-2/physiology , Virus Internalization , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Humans , Immune System/metabolism , Immune System/pathology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
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