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1.
Antimicrob Agents Chemother ; 66(8): e0008322, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-1938003

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent that has caused the current coronavirus disease (COVID) pandemic. Viral infection relies on the viral S (spike) protein/cellular receptor ACE2 interaction. Disrupting this interaction would lead to early blockage of viral replication. To identify chemical tools to further study these functional interfaces, 139,146 compounds from different chemical libraries were screened through an S/ACE2 in silico virtual molecular model. The best compounds were selected for further characterization using both cellular and biochemical approaches, reiterating SARS-CoV-2 entry and the S/ACE2 interaction. We report here two selected hits, bis-indolyl pyridine AB-00011778 and triphenylamine AB-00047476. Both of these compounds can block the infectivity of lentiviral vectors pseudotyped with the SARS-CoV-2 S protein as well as wild-type and circulating variant SARS-CoV-2 strains in various human cell lines, including pulmonary cells naturally susceptible to infection. AlphaLISA and biolayer interferometry confirmed a direct inhibitory effect of these drugs on the S/ACE2 association. A specific study of the AB-00011778 inhibitory properties showed that this drug inhibits viral replication with a 50% effective concentration (EC50) between 0.1 and 0.5 µM depending on the cell lines. Molecular docking calculations of the interaction parameters of the molecules within the S/ACE2 complex from both wild-type and circulating variants of the virus showed that the molecules may target multiple sites within the S/ACE2 interface. Our work indicates that AB-00011778 constitutes a good tool for modulating this interface and a strong lead compound for further therapeutic purposes.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Peptidyl-Dipeptidase A/pharmacology , Protein Binding , Pyridines/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
3.
Environ Sci Pollut Res Int ; 29(38): 57040-57053, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1899268

ABSTRACT

Obesity is a term that has recently been referred to describe a condition in which a person has become a diseased vessel. Obesity's internal pathology is too mysterious as it has a close resemblance with fatal diseases pathology. Obesity and coronavirus disease 2019 (COVID-19) are simultaneous epidemics declared by many organizations after observing their rampage in the recent world. Oxidative stress, cytokine storm, interleukin, and their contribution to the internal adipocyte environment implicated in the cascades of inflammatory pathology are portrayed here. Major determinants like angiotensin-converting enzyme 2 (ACE2) and renin-angiotensin-aldosterone system (RAAS) axis are highly sensitive molecular factors. Data from various countries suggested a clinical overview of how greater body mass index (BMI) is related to greater COVID-19 risk. It also gives insight into how obese individuals are obligately getting admitted and combating COVID-19 in intensive care unit including children less than 13 years of age under ultimate therapeutic options. There are numerous studies currently taking place for finding a cure for obesity which are mainly focused on natural resources and novel therapies like photobiomodulation (PBM) consisting of laser treatment, infrared treatment, etc. as current pharmacological treatments are reported to have fatal adverse effects. Finally, it is discussed how attenuating obesity will be a solution for future combat strategy. This review gives light on the areas of coagulation, inflammatory parameters, cardiometabolic complications, endothelial dysfunctions, immunological infirmity due to COVID-19 in obese individuals. A conceptual outline about correlation between the inflammatory pathophysiological steps triggering the aggravation of fatal consequences has been drawn in this review.


Subject(s)
COVID-19 , Child , Humans , Obesity , Peptidyl-Dipeptidase A/metabolism , Peptidyl-Dipeptidase A/pharmacology , Renin-Angiotensin System/physiology , SARS-CoV-2
4.
Nihon Yakurigaku Zasshi ; 157(2): 115-118, 2022.
Article in Japanese | MEDLINE | ID: covidwho-1714695

ABSTRACT

In the renin-angiotensin system (RAS), angiotensin II (AngII) converted by angiotensin converting enzyme (ACE) exerts a strong physiological activity via the AT1 receptor (AT1R). Thus, the ACE-AngII-AT1R axis positively regulates RAS. On the other hand, angiotensin converting enzyme 2 (ACE2) is known to negatively regulate RAS by degrading AngII into angiotensin 1-7 (Ang1-7). In the acute respiratory distress syndrome (ARDS), which is characterized by pulmonary hyperinflammation, the AngII-AT1R axis acts to exacerbate ARDS and the ACE2-AT2R axis acts protectively. More recently, ACE2 has been shown to be a receptor for SARS-CoV, the causative virus of severe acute respiratory syndrome (SARS), and SARS-CoV2, the causative virus of the 2019 coronavirus infection (COVID-19). Therefore, inhibition of the binding between ACE2 and virus spike protein is a drug discovery target for antiviral drugs against SARS-CoV and SARS-CoV2. In addition, when SARS and COVID-19 become severe, ARDS with cytokine storm is occured. We reported that soluble ACE2 protein and microbial-derived ACE2 like enzyme suppress pulmonary hyperinflammation due to SARS and COVID-19, respectively. In addition, it has been reported that the ACE2-soluble protein has an effect of suppressing the establishment of infection by inhibiting the binding between SARS-CoV2 and the cell membrane surface ACE2. Here, we describe the role of ACE2 in the pathophysiology of SARS/COVID-19 from the perspectives of inhibiting the progression to ARDS by suppressing pulmonary inflammation and suppressing the replication of the virus by inhibiting the binding of ACE2 to the spike protein.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , COVID-19/drug therapy , Humans , Peptidyl-Dipeptidase A/metabolism , Peptidyl-Dipeptidase A/pharmacology , RNA, Viral/metabolism , RNA, Viral/pharmacology , Renin-Angiotensin System/physiology , SARS-CoV-2
6.
J Cardiovasc Pharmacol Ther ; 25(4): 299-306, 2020 07.
Article in English | MEDLINE | ID: covidwho-144012

ABSTRACT

Coronavirus disease 19 (COVID-19) originated in Wuhan, China, in December 2019 has been declared pandemic by World Health Organization due to an exponential rise in the number of infected and deceased persons across the globe. Emerging reports suggest that susceptibility and mortality rates are higher in patients with certain comorbidities when compared to the average population. Cardiovascular diseases and diabetes are important risk factors for a lethal outcome of COVID-19. Extensive research ensuing the outbreak of coronavirus-related severe acute respiratory syndrome in the year 2003, and COVID-19 recently revealed a role of renin-angiotensin system (RAS) components in the entry of coronavirus wherein angiotensin-converting enzyme 2 (ACE2) had garnered the significant attention. This raises the question whether the use of RAS inhibitors, the backbone of treatment of cardiovascular, neurovascular, and kidney diseases could increase the susceptibility for coronavirus infection or unfortunate outcomes of COVID-19. Thus, currently, there is a lack of consensus regarding the effects of RAS inhibitors in such patients. Moreover, expert bodies like American Heart Association, American College of Cardiology, and so on have now released official statements that RAS inhibitors must be continued, unless suggested otherwise by a physician. In this brief review, we will elaborate on the role of RAS and ACE2 in pathogenesis of COVID-19. Moreover, we will discuss the potential effect of the use and disuse of RAS inhibitors in patients having COVID-19 with cardiometabolic comorbidities.


Subject(s)
Cardiovascular Diseases/drug therapy , Coronavirus Infections/physiopathology , Kidney Diseases/drug therapy , Peptidyl-Dipeptidase A/pharmacology , Pneumonia, Viral/physiopathology , Renin-Angiotensin System/physiology , Angiotensin-Converting Enzyme 2 , Betacoronavirus , COVID-19 , Comorbidity , Coronavirus Infections/drug therapy , Disease Susceptibility , Humans , Pandemics , Renin-Angiotensin System/drug effects , SARS-CoV-2
7.
Nat Commun ; 11(1): 2070, 2020 04 24.
Article in English | MEDLINE | ID: covidwho-116533

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, at the end of 2019, and there are currently no specific antiviral treatments or vaccines available. SARS-CoV-2 has been shown to use the same cell entry receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). In this report, we generate a recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1. A fusion protein containing an ACE2 mutant with low catalytic activity is also used in this study. The fusion proteins are then characterized. Both fusion proteins have a high binding affinity for the receptor-binding domains of SARS-CoV and SARS-CoV-2 and exhibit desirable pharmacological properties in mice. Moreover, the fusion proteins neutralize virus pseudotyped with SARS-CoV or SARS-CoV-2 spike proteins in vitro. As these fusion proteins exhibit cross-reactivity against coronaviruses, they have potential applications in the diagnosis, prophylaxis, and treatment of SARS-CoV-2.


Subject(s)
Betacoronavirus/drug effects , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin G/chemistry , Neutralization Tests , Peptidyl-Dipeptidase A/chemistry , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/metabolism , Binding, Competitive/drug effects , Cross Reactions , Drug Design , Humans , Immunoglobulin Fc Fragments/metabolism , Immunoglobulin Fc Fragments/pharmacology , Immunoglobulin G/metabolism , Immunoglobulin G/pharmacology , In Vitro Techniques , Inhibitory Concentration 50 , Membrane Fusion/drug effects , Mice , Mice, Inbred BALB C , Mutation , Peptide Fragments/chemistry , Peptide Fragments/genetics , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/pharmacokinetics , Peptidyl-Dipeptidase A/pharmacology , Protein Domains/genetics , Protein Stability , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/chemistry , Receptors, Virus/genetics , Receptors, Virus/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/pharmacokinetics , SARS Virus/drug effects , SARS Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
8.
Cell ; 181(4): 905-913.e7, 2020 05 14.
Article in English | MEDLINE | ID: covidwho-30638

ABSTRACT

We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A/pharmacology , Pneumonia, Viral/drug therapy , Recombinant Proteins/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Betacoronavirus/ultrastructure , Blood Vessels/virology , COVID-19 , Chlorocebus aethiops , Humans , Kidney/cytology , Kidney/virology , Mice , Organoids/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
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