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1.
Vascul Pharmacol ; 130: 106680, 2020 07.
Article in English | MEDLINE | ID: covidwho-1386723

ABSTRACT

Angiotensin-converting enzyme (ACE) and its homologue, ACE2, have been mostly associated with hypertensive disorder. However, recent pandemia of SARS-CoV-2 has put these proteins at the center of attention, as this virus has been shown to exploit ACE2 protein to enter cells. Clear difference in the response of affected patients to this virus has urged researchers to find the molecular basis and pathophysiology of the cell response to this virus. Different levels of expression and function of ACE proteins, underlying disorders, consumption of certain medications and the existence of certain genomic variants within ACE genes are possible explanations for the observed difference in the response of individuals to the SARS-CoV-2 infection. In the current review, we discuss the putative mechanisms for this observation.


Subject(s)
Coronavirus Infections/enzymology , Peptidyl-Dipeptidase A/biosynthesis , Pneumonia, Viral/enzymology , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Humans , Pandemics , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology
3.
Clin Sci (Lond) ; 134(21): 2851-2871, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-1177131

ABSTRACT

Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin-angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer's dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure-function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect-host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Receptors, Virus/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Conformation , Receptors, Virus/chemistry , SARS-CoV-2 , Structure-Activity Relationship
4.
Bratisl Lek Listy ; 121(11): 775-778, 2020.
Article in English | MEDLINE | ID: covidwho-1034642

ABSTRACT

COVID-19 ‒ a coronavirus disease, affected almost all countries in the world. It is a new virus disease, nobody has prior immunity to it, human population is prone to infections. In March 11 2020, WHO declared the pandemic status. The main symptoms include: fever, dry cough and fatigue. Virus proteins need mitochondrial energy for their own survival and replication. Upon viral infections, mitochondrial dynamics and metabolism can be modulated, which can influence the energy production in the host cells. Coenzyme Q10 is an integral component of mitochondrial respiratory chain and the key component of mitochondrial ATP production. The exact pathobiochemical mechanism of the disease is unknown. Modulated mitochondrial dynamics and metabolism with lower CoQ10 levels in viral infections leads us to the hypothesis that one of the main pathobiochemical effects of SARS-Cov-2 virus could be mitochondrial bioenergetics dysfunction with CoQ10 deficit leading to the reduction of its endogenous biosynthesis. The mechanism might be virus induced oxidative stress causing a mutation of one or more of the nine COQ genes, resulting in primary CoQ10 deficiency. New perspective for patients with COVID-19 may be supportive targeting therapy with coenzyme Q10 to increase the energy production, immunity and decrease oxidative stress (Fig. 1, Ref. 51). Keywords: COVID-19, virus, mitochondrial bioenergetics, coenzyme Q10, oxidative stress.


Subject(s)
Coronavirus Infections/enzymology , Energy Metabolism , Mitochondria/enzymology , Pneumonia, Viral/enzymology , Ubiquinone/analogs & derivatives , Betacoronavirus , COVID-19 , Humans , Pandemics , SARS-CoV-2 , Ubiquinone/genetics
5.
Bratisl Lek Listy ; 121(11): 786-788, 2020.
Article in English | MEDLINE | ID: covidwho-1034641

ABSTRACT

Our understanding of the mechanisms responsible for death of aged people from Covid-19 became one of the major concerns of these days. Glucose-6-phosphate dehydrogenase (G6PD) enhances the normal senescence and accelerates the precocious removal of chronologically young, yet biologically aged cells. Thus, its deficiency is associated with an increase in the cellular oxidative stress. Accumulating evidence showed that oxidative stress has a fundamental role in several age-related diseases. Nowadays, Covid-19 is considered a serious health problem worldwide. The host cellular environment is the key determinant of pathogen Infectivity. Most respiratory viral infections have a strong association with Glucose-6-phosphate dehydrogenase. Unfortunately, this enzyme deficiency markedly decreases with aging what is involved in increasing of the morbidity rate. The aim of this mini review was to shed more light on the role of G6PD deficiency in aged people infected with Covid-19 (Ref. 20). Keywords: GSPD, Covid-19, elderly people.


Subject(s)
Coronavirus Infections/enzymology , Glucosephosphate Dehydrogenase Deficiency , Pneumonia, Viral/enzymology , Aged , Betacoronavirus , COVID-19 , Glucosephosphate Dehydrogenase , Glucosephosphate Dehydrogenase Deficiency/epidemiology , Humans , Pandemics , SARS-CoV-2
7.
Eur J Gastroenterol Hepatol ; 32(12): 1523-1526, 2020 12.
Article in English | MEDLINE | ID: covidwho-1020322

ABSTRACT

OBJECTIVES: Recent guidelines for celiac disease have allowed a biopsy-free approach in endomysial antibodies (EMAs) positive children with high antitransglutaminase (TGA-IgA) titer [>10 time upper limit of normal (ULN)]. Esophagogastroduodenoscopy is still necessary for diagnosis in children with lower title. Because elective pediatric endoscopy has been substantially shouted down during coronavirus disease (COVID-19) pandemic, many children remained undiagnosed - and therefore untreated - for a long time. We aimed to analyze the feasibility and accuracy of a biopsy-free approach in suspected celiac disease children with TGA-IgA values <10 ULN to facilitate the diagnostic process by avoiding endoscopy. METHODS: In this study cohort, we retrospectively analyzed all biopsy-confirmed diagnosis of celiac disease in our center (between 2014 and 2019). The positive predictive value (PPV) of TGA-IgA titers between 5 and 10 ULN and positive EMA in diagnosing celiac disease were determined. Mucosal atrophy and resolution of symptoms after gluten-free diet (GFD) were considered to confirm initial diagnosis. RESULTS: Of 430 celiac disease patients (F: 274; mean age 7.54 years) diagnosed by endoscopy, 84 (F: 46; mean age 8 years) with TGA-IgA between 5 and 10 ULN and positive EMA were identified. The PPV of TGA-IgA between 5 and 10 ULN and positive EMA was 0.93 (95% confidence interval 0.90-0.96). All these children had a symptom resolution and antibodies normalization after GFD. CONCLUSION: During the COVID-19 outbreak, a temporarily reduction of the TGA-IgA threshold for biopsy-sparing approach seems feasible in EMA positive children with TGA-IgA between 5 and 10 ULN.


Subject(s)
Autoantibodies/blood , Betacoronavirus , Celiac Disease/diagnosis , Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Practice Guidelines as Topic , Transglutaminases/immunology , Autoantibodies/immunology , Biopsy , COVID-19 , Celiac Disease/epidemiology , Celiac Disease/immunology , Child , Comorbidity , Coronavirus Infections/enzymology , Coronavirus Infections/immunology , Endoscopy, Digestive System , Female , Humans , Male , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/immunology , Retrospective Studies , SARS-CoV-2 , Transglutaminases/blood
8.
Br J Pharmacol ; 177(21): 4887-4898, 2020 11.
Article in English | MEDLINE | ID: covidwho-998833

ABSTRACT

Several lines of evidence support a link between the essential element zinc and the coronavirus disease 2019 (COVID-19). An important fact is that zinc is present in proteins of humans and of viruses. Some zinc sites in viral enzymes may serve as drug targets and may liberate zinc ions, thus leading to changes in intracellular concentration of zinc ions, while increased intracellular zinc may induce biological effects in both the host and the virus. Drugs such as chloroquine may contribute to increased intracellular zinc. Moreover, clinical trials on the use of zinc alone or in addition to other drugs in the prophylaxis/treatment of COVID-19 are ongoing. Thereby, we aim to discuss the rationale for targeting zinc metalloenzymes as a new strategy for the treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Subject(s)
Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Zinc/metabolism , Betacoronavirus/isolation & purification , COVID-19 , Chloroquine/pharmacology , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Enzymes/metabolism , Humans , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , SARS-CoV-2
9.
Br J Pharmacol ; 177(21): 4825-4844, 2020 11.
Article in English | MEDLINE | ID: covidwho-998826

ABSTRACT

Angiotensin Converting Enzyme2 is the cell surface binding site for the coronavirus SARS-CoV-2, which causes COVID-19. We propose that an imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing angiotensin II (Ang II) signalling is primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of Ang II to Ang peptides that counteract pathophysiological effects of ACE1-generated ANG II. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: (a) AT receptor antagonists; (b) ACE1 inhibitors (ACEIs); (iii) agonists of receptors activated by ACE2-derived peptides (e.g. Ang (1-7), which activates MAS1); (d) recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved AT antagonists and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Betacoronavirus/enzymology , COVID-19 , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Drug Repositioning , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , SARS-CoV-2
10.
Braz. arch. biol. technol ; 63: e20200304, 2020. tab, graf
Article in English | WHO COVID, LILACS (Americas) | ID: covidwho-914314

ABSTRACT

Abstract We aimed to analyze the expression profile of ACE2 and similar genes with ACE2, predict the number of variations in ACE2, detect the suspected SNPs on ACE2 gene, and perform the pathway analysis of renin-angiotensin system (RAS) and protein absorption-digestion. Moreover, we have predicted the gene-related diseases with ACE2. STRING was used to analyze functionally similar genes with ACE2. Exome Variant Server, SIFT, Polyphen2 were used to predict the number of variations in ACE2 and detect the suspected SNPs on ACE2. KEGG database and STRING were used to draw pathway of ACE2. Then, DISEASES resource, FitSNPs, UniProt, BioXpress, IGV Browser, Ensembl Genome Browser, and UCSC Genome Browser were used to predict the ACE2 gene-related diseases and expression profile in human normal and cancer tissues. We have shown that expression of ACE2 was correlated with AGT, REN, AGTR1, AGRT2, MME2, DPP4, PRCP, MEP1A, XPNPEP2, MEP1BandACE2 is expressed in testis, kidney, heart, thyroid, colon, esophagus, breast, minor salivary gland, pancreas, lung, liver, bladder, cervix, and muscle tissues. We found 99 variations in ACE2 gene, in which no previous study has been performed. In the future, this in silico analysis should be combined with other pieces of evidence including experimental data to assign function.


Subject(s)
Humans , Pneumonia, Viral/enzymology , Coronavirus Infections/enzymology , Peptidyl-Dipeptidase A/genetics , Pandemics , Renin-Angiotensin System/genetics , Gene Expression , Genotype
11.
Int J Mol Sci ; 21(21)2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-909306

ABSTRACT

Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus-host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein-protein interfaces responsible for virus entry and infection transmission.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2 , Binding Sites , COVID-19 , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Host Microbial Interactions , Humans , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Protein Binding , Protein Domains , Receptors, Virus/metabolism , SARS-CoV-2 , Signal Transduction , Virus Internalization
12.
Acta Pharm ; 71(2): 163-174, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-910384

ABSTRACT

The current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today's diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.


Subject(s)
Coronavirus Infections/enzymology , Pneumonia, Viral/enzymology , Protease Inhibitors/pharmacology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacology , Alanine/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19 , Coronavirus Infections/drug therapy , Crystallography, X-Ray , Drug Discovery/methods , Drug Repositioning , Humans , Models, Chemical , Molecular Docking Simulation , Molecular Structure , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/chemistry , Structure-Activity Relationship
13.
Arq. bras. cardiol ; 114(5): 817-822, maio 2020. graf
Article in Portuguese | WHO COVID, LILACS (Americas) | ID: covidwho-910582

ABSTRACT

Resumo A doença de coronavírus 2019 (COVID-19) é uma pandemia global afetando o mundo, estando presente em mais de 1.300.000 pacientes. O COVID-19 age pelo receptor da enzima conversora de angiotensina 2 (ECA2). As comorbidades cardiovasculares são mais frequentes com COVID-19, e cerca 10% de casos desenvolvem miocardite (22% de pacientes críticas). Mais pesquisas serão necessárias para continuar ou descontinuar inibidores de ECA e bloqueadores dos receptores da angiotensina, que são essenciais para hipertensão e insuficiência cardíaca em COVID-19. Pesquisa intensiva é promissora para o tratamento e a prevenção da COVID-19.


Abstract Coronavirus disease 2019 (COVID-19) is a global pandemic affecting the world, seen in more than 1,300,000 patients. COVID-19 acts through the angiotensin-converting enzyme 2 (ACE2) receptor. Cardiovascular comorbidities are more common with COVID-19, and nearly 10% of cases develop myocarditis (22% of critical patients). Further research is needed to continue or discontinue ACE inhibitors and angiotensin receptor blockers, which are essential in hypertension and heart failure in COVID-19. Intensive research is promising for the treatment and prevention of COVID-19.


Subject(s)
Humans , Animals , Pneumonia, Viral/epidemiology , Cardiovascular Diseases/epidemiology , Coronavirus Infections/epidemiology , Betacoronavirus , Antiviral Agents/therapeutic use , Pneumonia, Viral/enzymology , Pneumonia, Viral/mortality , Pneumonia, Viral/drug therapy , Cardiovascular Diseases/enzymology , Cardiovascular Diseases/mortality , Comorbidity , China/epidemiology , Chloroquine/therapeutic use , Coronavirus Infections , Coronavirus Infections/enzymology , Coronavirus Infections/mortality , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A/metabolism , Antirheumatic Agents/therapeutic use , Angiotensin Receptor Antagonists/metabolism , Pandemics , Hypertension/enzymology , Hypertension/epidemiology
14.
Am J Respir Cell Mol Biol ; 63(5): 571-590, 2020 11.
Article in English | MEDLINE | ID: covidwho-901528

ABSTRACT

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.


Subject(s)
Acute Lung Injury/drug therapy , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Lung/drug effects , Pneumonia, Viral/drug therapy , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Acute Lung Injury/enzymology , Acute Lung Injury/virology , Animals , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Lung/enzymology , Lung/virology , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , SARS-CoV-2 , Signal Transduction/drug effects
15.
Clin Sci (Lond) ; 134(21): 2791-2805, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-899997

ABSTRACT

Angiotensin-converting enzyme II (ACE2) is a homologue of angiotensin-converting enzyme discovered in 2000. From the initial discovery, it was recognized that the kidneys were organs very rich on ACE2. Subsequent studies demonstrated the precise localization of ACE2 within the kidney and the importance of this enzyme in the metabolism of Angiotensin II and the formation of Angiotensin 1-7. With the recognition early in 2020 of ACE2 being the main receptor of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the interest in this protein has dramatically increased. In this review, we will focus on kidney ACE2; its localization, its alterations in hypertension, diabetes, the effect of ACE inhibitors and angiotensin type 1 receptor blockers (ARBs) on ACE2 and the potential use of ACE2 recombinant proteins therapeutically for kidney disease. We also describe the emerging kidney manifestations of COVID-19, namely the frequent development of acute kidney injury. The possibility that binding of SARS-CoV-2 to kidney ACE2 plays a role in the kidney manifestations is also briefly discussed.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/enzymology , Kidney Diseases/enzymology , Kidney/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Receptors, Virus/metabolism , Acute Kidney Injury/enzymology , Acute Kidney Injury/virology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Diabetes Mellitus/enzymology , Diabetes Mellitus/physiopathology , History, 21st Century , Host-Pathogen Interactions , Humans , Hypertension/enzymology , Hypertension/physiopathology , Kidney/physiopathology , Kidney Diseases/drug therapy , Kidney Diseases/physiopathology , Pandemics , Peptidyl-Dipeptidase A/history , Peptidyl-Dipeptidase A/therapeutic use , Pneumonia, Viral/virology , Receptors, Virus/history , SARS-CoV-2
16.
Clin Sci (Lond) ; 134(21): 2823-2833, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-899996

ABSTRACT

ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.


Subject(s)
Amino Acid Transport Systems, Neutral/metabolism , Betacoronavirus/pathogenicity , Coronavirus Infections/enzymology , Intestinal Absorption , Intestinal Mucosa/enzymology , Membrane Transport Proteins/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/virology , Protein Multimerization , SARS-CoV-2
17.
Drug Discov Ther ; 14(5): 256-258, 2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-895583

ABSTRACT

In the ongoing coronavirus diseases-2019 (COVID-19) crisis that caused immense suffering and deaths, the choice of therapy for the prevention and life-saving conditions must be based on sound scientific evidence. Uncertainty and apprehension are exacerbated in people using angiotensin-converting enzyme (ACE) inhibitors to control their comorbidities such as hypertension and diabetes. These drugs are reported to result in unfavorable outcome as they tend to increase the levels of ACE2 which mediates the entry of SARS-CoV-2. Amiloride, a prototypic inhibitor of epithelial sodium channels (ENaC) can be an ideal candidate for COVID-19 patients, given its ACE reducing and cytosolic pH increasing effects. Moreover, its potassium-sparing and anti-epileptic activities make it a promising alternative or a combinatorial agent.


Subject(s)
Amiloride/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Epithelial Sodium Channel Blockers/pharmacology , Pneumonia, Viral/drug therapy , Respiratory Mucosa/drug effects , Virus Internalization/drug effects , A549 Cells , Angiotensin-Converting Enzyme 2 , Betacoronavirus/pathogenicity , COVID-19 , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/enzymology , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Down-Regulation , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Respiratory Mucosa/enzymology , Respiratory Mucosa/virology , SARS-CoV-2
18.
Clin Sci (Lond) ; 134(19): 2645-2664, 2020 10 16.
Article in English | MEDLINE | ID: covidwho-872746

ABSTRACT

The virulence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the aggressive nature of the disease has transformed the universal pace of research in the desperate attempt to seek effective therapies to halt the morbidity and mortality of this pandemic. The rapid sequencing of the SARS-CoV-2 virus facilitated identification of the receptor for angiotensin converting enzyme 2 (ACE2) as the high affinity binding site that allows virus endocytosis. Parallel evidence that coronavirus disease 2019 (COVID-19) disease evolution shows greater lethality in patients with antecedent cardiovascular disease, diabetes, or even obesity questioned the potential unfavorable contribution of angiotensin converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers as facilitators of adverse outcomes due to the ability of these therapies to augment the transcription of Ace2 with consequent increase in protein formation and enzymatic activity. We review, here, the specific studies that support a role of these agents in altering the expression and activity of ACE2 and underscore that the robustness of the experimental data is associated with weak clinical long-term studies of the existence of a similar regulation of tissue or plasma ACE2 in human subjects.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral/virology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , SARS-CoV-2 , Time Factors
19.
Am J Physiol Heart Circ Physiol ; 319(5): H1059-H1068, 2020 11 01.
Article in English | MEDLINE | ID: covidwho-842301

ABSTRACT

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly reached pandemic proportions, and knowledge about this virus and coronavirus disease 2019 (COVID-19) has expanded rapidly. This review focuses primarily on mechanisms that contribute to acute cardiac injury and dysfunction, which are common in patients with severe disease. The etiology of cardiac injury is multifactorial, and the extent is likely enhanced by preexisting cardiovascular disease. Disruption of homeostatic mechanisms secondary to pulmonary pathology ranks high on the list, and there is growing evidence that direct infection of cardiac cells can occur. Angiotensin-converting enzyme 2 (ACE2) plays a central role in COVID-19 and is a necessary receptor for viral entry into human cells. ACE2 normally not only eliminates angiotensin II (Ang II) by converting it to Ang-(1-7) but also elicits a beneficial response profile counteracting that of Ang II. Molecular analyses of single nuclei from human hearts have shown that ACE2 is most highly expressed by pericytes. Given the important roles that pericytes have in the microvasculature, infection of these cells could compromise myocardial supply to meet metabolic demand. Furthermore, ACE2 activity is crucial for opposing adverse effects of locally generated Ang II, so virus-mediated internalization of ACE2 could exacerbate pathology by this mechanism. While the role of cardiac pericytes in acute heart injury by SARS-CoV-2 requires investigation, expression of ACE2 by these cells has broader implications for cardiac pathophysiology.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/enzymology , Heart Diseases/enzymology , Peptidyl-Dipeptidase A/metabolism , Pericytes/enzymology , Pneumonia, Viral/enzymology , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/virology , Heart Diseases/physiopathology , Heart Diseases/virology , Host-Pathogen Interactions , Humans , Pandemics , Pericytes/virology , Pneumonia, Viral/virology , SARS-CoV-2
20.
Comput Biol Med ; 126: 104046, 2020 11.
Article in English | MEDLINE | ID: covidwho-837907

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (Mpro), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcumin as Mpro inhibitors with binding energies of -9.7 and -9.2 kcal/mol, respectively. Binding mode analysis demonstrated the ability of salvianolic acid A and curcumin to form nine and six hydrogen bonds, respectively with amino acids proximal to Mpro's active site. Stabilities and binding affinities of the two identified natural spices were calculated over 40 ns molecular dynamics simulations and compared to an antiviral protease inhibitor (lopinavir). Molecular mechanics-generalized Born surface area energy calculations revealed greater salvianolic acid A affinity for the enzyme over curcumin and lopinavir with energies of -44.8, -34.2 and -34.8 kcal/mol, respectively. Using a STRING database, protein-protein interactions were identified for salvianolic acid A included the biochemical signaling genes ACE, MAPK14 and ESR1; and for curcumin, EGFR and TNF. This study establishes salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease and provides a promising inhibitor lead for in vitro enzyme testing.


Subject(s)
Betacoronavirus/enzymology , Caffeic Acids/chemistry , Coronavirus Infections/drug therapy , Curcumin/chemistry , Cysteine Endopeptidases , Drug Discovery , Lactates/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Pneumonia, Viral/drug therapy , Protease Inhibitors/chemistry , Viral Nonstructural Proteins , COVID-19 , Caffeic Acids/therapeutic use , Coronavirus 3C Proteases , Coronavirus Infections/enzymology , Curcumin/therapeutic use , Cysteine Endopeptidases/chemistry , Humans , Lactates/therapeutic use , Pandemics , Pneumonia, Viral/enzymology , Protease Inhibitors/therapeutic use , SARS-CoV-2 , Thermodynamics , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry
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