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1.
Biosensors (Basel) ; 12(11)2022 Nov 07.
Article in English | MEDLINE | ID: covidwho-2109934

ABSTRACT

Rapid and cost-effective diagnostic tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a critical and valuable weapon for the coronavirus disease 2019 (COVID-19) pandemic response. SARS-CoV-2 invasion is primarily mediated by human angiotensin-converting enzyme 2 (hACE2). Recent developments in ACE2-based SARS-CoV-2 detection modalities accentuate the potential of this natural host-virus interaction for developing point-of-care (POC) COVID-19 diagnostic systems. Although research on harnessing ACE2 for SARS-CoV-2 detection is in its infancy, some interesting biosensing devices have been developed, showing the commercial viability of this intriguing new approach. The exquisite performance of the reported ACE2-based COVID-19 biosensors provides opportunities for researchers to develop rapid detection tools suitable for virus detection at points of entry, workplaces, or congregate scenarios in order to effectively implement pandemic control and management plans. However, to be considered as an emerging approach, the rationale for ACE2-based biosensing needs to be critically and comprehensively surveyed and discussed. Herein, we review the recent status of ACE2-based detection methods, the signal transduction principles in ACE2 biosensors and the development trend in the future. We discuss the challenges to development of ACE2-biosensors and delineate prospects for their use, along with recommended solutions and suggestions.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , COVID-19/diagnosis , SARS-CoV-2 , Peptidyl-Dipeptidase A/physiology , Pandemics
2.
Biomolecules ; 12(11)2022 Nov 10.
Article in English | MEDLINE | ID: covidwho-2109922

ABSTRACT

With its fast-paced mutagenesis, the SARS-CoV-2 Omicron variant has threatened many societies worldwide. Strategies for predicting mutagenesis such as the computational prediction of SARS-CoV-2 structural diversity and its interaction with the human receptor will greatly benefit our understanding of the virus and help develop therapeutics against it. We aim to use protein structure prediction algorithms along with molecular docking to study the effects of various mutations in the Receptor Binding Domain (RBD) of the SARS-CoV-2 and its key interactions with the angiotensin-converting enzyme 2 (ACE-2) receptor. The RBD structures of the naturally occurring variants of SARS-CoV-2 were generated from the WUHAN-Hu-1 using the trRosetta algorithm. Docking (HADDOCK) and binding analysis (PRODIGY) between the predicted RBD sequences and ACE-2 highlighted key interactions at the Receptor-Binding Motif (RBM). Further mutagenesis at conserved residues in the Original, Delta, and Omicron variants (P499S and T500R) demonstrated stronger binding and interactions with the ACE-2 receptor. The predicted T500R mutation underwent some preliminary tests in vitro for its binding and transmissibility in cells; the results correlate with the in-silico analysis. In summary, we suggest conserved residues P499 and T500 as potential mutation sites that could increase the binding affinity and yet do not exist in nature. This work demonstrates the use of the trRosetta algorithm to predict protein structure and future mutations at the RBM of SARS-CoV-2, followed by experimental testing for further efficacy verification. It is important to understand the protein structure and folding to help develop potential therapeutics.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , COVID-19/genetics , Spike Glycoprotein, Coronavirus/chemistry , Molecular Docking Simulation , Peptidyl-Dipeptidase A/chemistry , Receptors, Virus , Protein Binding , Mutation , Protein Folding
3.
Commun Biol ; 5(1): 1188, 2022 Nov 05.
Article in English | MEDLINE | ID: covidwho-2106511

ABSTRACT

SARS-CoV-2 has evolved continuously and accumulated spike mutations with each variant having a different binding for the cellular ACE2 receptor. It is not known whether the interactions between such mutated spikes and ACE2 glycans are conserved among different variant lineages. Here, we focused on three ACE2 glycosylation sites (53, 90 and 322) that are geometrically close to spike binding sites and investigated the effect of their glycosylation pattern on spike affinity. These glycosylation deletions caused distinct site-specific changes in interactions with the spike and acted cooperatively. Of note, the particular interaction profiles were conserved between the SARS-CoV-2 parental virus and the variants of concern (VOCs) Delta and Omicron. Our study provides insights for a better understanding of the importance of ACE2 glycosylation on ACE2/SARS-CoV-2 spike interaction and guidance for further optimization of soluble ACE2 for therapeutic use.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/genetics , SARS-CoV-2/genetics , Glycosylation , Peptidyl-Dipeptidase A , Protein Binding
4.
Commun Biol ; 5(1): 1170, 2022 Nov 03.
Article in English | MEDLINE | ID: covidwho-2106509

ABSTRACT

The trimeric spike (S) glycoprotein, which protrudes from the SARS-CoV-2 viral envelope, binds to human ACE2, initiated by at least one protomer's receptor binding domain (RBD) switching from a "down" (closed) to an "up" (open) state. Here, we used large-scale molecular dynamics simulations and two-dimensional replica exchange umbrella sampling calculations with more than a thousand windows and an aggregate total of 160 µs of simulation to investigate this transition with and without glycans. We find that the glycosylated spike has a higher barrier to opening and also energetically favors the down state over the up state. Analysis of the S-protein opening pathway reveals that glycans at N165 and N122 interfere with hydrogen bonds between the RBD and the N-terminal domain in the up state, while glycans at N165 and N343 can stabilize both the down and up states. Finally, we estimate how epitope exposure for several known antibodies changes along the opening path. We find that the BD-368-2 antibody's epitope is continuously exposed, explaining its high efficacy.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2 , Peptidyl-Dipeptidase A , Polysaccharides , Epitopes
5.
Indian J Pathol Microbiol ; 65(4): 902-906, 2022.
Article in English | MEDLINE | ID: covidwho-2100021

ABSTRACT

COVID-19 pandemic caused by SARS-CoV-2 virus has been around for 2 years causing significant health-care catastrophes in most parts of the world. The understanding of COVID-19 continues to expand, with multiple newer developments such as the presence of asymptomatic cases, feco-oral transmission, and endothelial dysfunction. The existing classification was developed before this current understanding. With the availability of recent literature evidences, we have attempted a classification encompassing pathogenesis and clinical features for better understanding of the disease process. The pathogenesis of COVID-19 continues to evolve. The spiked protein of the SARS-CoV-2 virus binds to ACE2 receptors causes direct cytopathic damage and hyperinflammatory injury. In addition to alveolar cells, ACE2 is also distributed in gastrointestinal tract and vascular endothelium. ACE2-SARS-CoV-2 interaction engulfs the receptors leading to depletion. Accumulation of Ang2 via AT1 receptor (AT1R) binding causes upregulation of macrophage activity leading to pro-inflammatory cytokine release. Interleukin-6 (IL-6) has been attributed to cause hyperinflammatory syndrome in COVID-19. In addition, it also causes severe widespread endothelial injury through soluble IL-6 receptors. Thrombotic complications occur following the cleavage and activation of von Willebrand factor. Based on the above understanding, clinical features, organ involvement, risk stratification, and disease severity, we have classified COVID-19 patients into asymptomatic, pulmonary, GI, and systemic COVID-19 (S-COVID-19). Studies show that the infectivity and prognosis are different and distinct amongst these groups. Systemic-COVID-19 patients are more likely to be critically ill with multi-organ dysfunction and thrombo-embolic complications.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Pandemics , Angiotensin-Converting Enzyme 2 , Peptidyl-Dipeptidase A/metabolism
6.
Molecules ; 27(21)2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2099670

ABSTRACT

Since there is an urgent need for novel treatments to combat the current coronavirus disease 2019 (COVID-19) pandemic, in silico molecular docking studies were implemented as an attempt to explore the ability of selected bioactive constituents of extra virgin olive oil (EVOO) to act as potent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antiviral compounds, aiming to explore their ability to interact with SARS-CoV-2 Spike key therapeutic target protein. Our results suggest that EVOO constituents display substantial capacity for binding and interfering with Spike (S) protein, both wild-type and mutant, via the receptor-binding domain (RBD) of Spike, or other binding targets such as angiotensin-converting enzyme 2 (ACE2) or the RBD-ACE2 protein complex, inhibiting the interaction of the virus with host cells. This in silico study provides useful insights for the understanding of the mechanism of action of the studied compounds at a molecular level. From the present study, it could be suggested that the studied active phytochemicals could potentially inhibit the Spike protein, contributing thus to the understanding of the role that they can play in future drug designing and the development of anti-COVID-19 therapeutics.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Olive Oil , Molecular Docking Simulation , COVID-19/drug therapy , Peptidyl-Dipeptidase A/metabolism , Binding Sites , Protein Binding
7.
Int J Mol Sci ; 23(21)2022 Nov 07.
Article in English | MEDLINE | ID: covidwho-2099582

ABSTRACT

Autoimmune thyroid diseases (AITDs), which include Hashimoto's thyroiditis (HT) and Graves' disease (GD), have a higher prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the literature. The effects of AITD-associated cytokines on SARS-CoV-2 infection-mediating molecule levels might be involved in the pathogenesis of susceptibility. We speculated that hydrogen sulfide (H2S) might attenuate this process since H2S has antiviral effects. Using immunohistochemistry, we found that angiotensin-converting enzyme-II (ACE2) expression was higher in the HT group and neuropilin 1 (NRP1) expression was higher in HT and GD groups than in the normal group, while transmembrane protease serine type 2 (TMPRSS2) expression was lower in HT and GD groups. When culturing primary thyrocytes with cytokines or sodium hydrosulfide (NaHS) plus cytokines, we found that ACE2 and NRP1 mRNA levels were upregulated while TMPRSS2 levels were downregulated by interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). After pretreatment with NaHS in thyrocytes, ACE2 and NRP1 expression were downregulated compared to IFN-γ or TNF-α treatment, and NaHS had no effect on TMPRSS2 expression. Our findings suggested that IFN-γ and TNF-α, which are elevated in AITDs, promoted ACE2 and NRP1 expression and inhibited TMPRSS2 expression. H2S might protect against SARS-CoV-2 infection by downregulating ACE2 and NRP1 levels.


Subject(s)
COVID-19 , Graves Disease , Hydrogen Sulfide , Humans , SARS-CoV-2 , Tumor Necrosis Factor-alpha/pharmacology , Interferon-gamma/pharmacology , Angiotensin-Converting Enzyme 2/genetics , Hydrogen Sulfide/pharmacology , Peptidyl-Dipeptidase A/metabolism
8.
Int J Mol Sci ; 23(21)2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2099578

ABSTRACT

SARS-CoV-2 is a rapidly evolving pathogen that has caused a global pandemic characterized by several consecutive waves. Based on epidemiological and NGS data, many different variants of SARS-CoV-2 were described and characterized since the original variant emerged in Wuhan in 2019. Notably, SARS-CoV-2 variants differ in transmissibility and pathogenicity in the human population, although the molecular basis for this difference is still debatable. A significant role is attributed to amino acid changes in the binding surface of the Spike protein to the ACE2 receptor, which may facilitate virus entry into the cell or contribute to immune evasion. We modeled in silico the interaction between Spike RBDs of Wuhan-Hu-1, Delta, and Omicron BA.1 variants and ACE2 at different pHs (pH 5 and pH 7) and showed that the strength of this interaction was higher for the Omicron BA.1 RBD compared to Wuhan-Hu-1 or Delta RBDs and that the effect was more profound at pH 5. This finding is strikingly related to the increased ability of Omicron variants to spread in the population. We also noted that during its spread in the population, SARS-CoV-2 evolved to a more charged, basic composition. We hypothesize that the more basic surface of the Omicron variant may facilitate its spread in the upper respiratory tract but not in the lower respiratory tract, where pH estimates are different. We calculated the amyloidogenic properties of Spike RBDs in different SARS-CoV-2 variants and found eight amyloidogenic regions in the Spike RBDs for each of the variants predicted by the FoldAmyloid program. Although all eight regions were almost identical in the Wuhan to Gamma variants, two of them were significantly longer in both Omicron variants, making the Omicron RBD more amyloidogenic. We discuss how the increased predicted amyloidogenicity of the Omicron variants RBDs may be important for protein stability, influence its interaction with ACE2 and contribute to immune evasion.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Angiotensin-Converting Enzyme 2/genetics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Hydrogen-Ion Concentration
9.
Biomolecules ; 12(11)2022 Oct 31.
Article in English | MEDLINE | ID: covidwho-2099330

ABSTRACT

After the SARS-CoV-2 Wuhan variant that gave rise to the pandemic, other variants named Delta, Omicron, and Omicron-2 sequentially became prevalent, with mutations spread around the viral genome, including on the spike (S) protein; in order to understand the resultant in gains in infectivity, we interrogated in silico both the equilibrium binding and the binding pathway of the virus' receptor-binding domain (RBD) to the angiotensin-converting enzyme 2 (ACE2) receptor. We interrogated the molecular recognition between the RBD of different variants and ACE2 through supervised molecular dynamics (SuMD) and classic molecular dynamics (MD) simulations to address the effect of mutations on the possible S protein binding pathways. Our results indicate that compensation between binding pathway efficiency and stability of the complex exists for the Omicron BA.1 receptor binding domain, while Omicron BA.2's mutations putatively improved the dynamic recognition of the ACE2 receptor, suggesting an evolutionary advantage over the previous strains.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , Angiotensin-Converting Enzyme 2/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Protein Binding , Peptidyl-Dipeptidase A/chemistry , COVID-19/genetics , Receptors, Virus/genetics , Mutation
10.
Front Immunol ; 13: 1001951, 2022.
Article in English | MEDLINE | ID: covidwho-2099151

ABSTRACT

Various species of the SARS-CoV-2 host cell receptor, the angiotensin-converting enzyme 2 (ACE2), are present in serum, which may result from virus entry and subsequent proteolytic processing of the membrane receptor. We have recently demonstrated changes of particular ACE2 species in virus infected humans, either cleaved fragments or circulating full-length species. Here, we further explore the potential of serum ACE2 as a biomarker to test SARS-CoV-2 infection and vaccine efficacy in virus susceptible transgenic K18-hACE2 mice expressing human ACE2. First, in serum samples derived from K18-hACE2 mice challenged with a lethal dose of SARS-CoV-2, we observed an increase in the levels of cleaved ACE2 fragment at day 2 post-challenge, which may represent the subsequent proteolytic processing through virus entry. These elevated levels were maintained until the death of the animals at day 6 post-challenge. The circulating full-length ACE2 form displayed a sizable peak at day 4, which declined at day 6 post-challenge. Noticeably, immunization with two doses of the MVA-CoV2-S vaccine candidate prevented ACE2 cleaved changes in serum of animals challenged with a lethal dose of SARS-CoV-2. The efficacy of the MVA-CoV2-S was extended to vaccinated mice after virus re-challenge. These findings highlight that ACE2 could be a potential serum biomarker for disease progression and vaccination against SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Animals , Humans , Mice , Biomarkers , COVID-19/prevention & control , Mice, Transgenic , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Vaccine Efficacy
11.
Front Immunol ; 13: 999534, 2022.
Article in English | MEDLINE | ID: covidwho-2099150

ABSTRACT

Up to now, coronavirus disease 2019 (COVID-19) is still affecting worldwide due to its highly infectious nature anrapid spread. Diabetic kidney disease (DKD) is an independent risk factor for severe COVID-19 outcomes, and they have a certain correlation in some aspects. Particularly, the activated renin-angiotensin-aldosterone system, chronic inflammation, endothelial dysfunction, and hypercoagulation state play an important role in the underlying mechanism linking COVID-19 to DKD. The dipeptidyl peptidase-4 inhibitor is considered a potential therapy for COVID-19 and has similarly shown organ protection in DKD. In addition, neuropilin-1 as an alternative pathway for angiotensin-converting enzyme 2 also contributes to severe acute respiratory syndrome coronavirus 2 entering the host cells, and its decreased expression can affect podocyte migration and adhesion. Here, we review the pathogenesis and current evidence of the interaction of DKD and COVID-19, as well as focus on elevated blood glucose following vaccination and its possible mechanism. Grasping the pathophysiology of DKD patients with COVID-19 is of great clinical significance for the formulation of therapeutic strategies.


Subject(s)
COVID-19 , Diabetes Mellitus , Diabetic Nephropathies , Vaccines , Humans , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2
12.
Chem Commun (Camb) ; 58(93): 12939-12942, 2022 Nov 22.
Article in English | MEDLINE | ID: covidwho-2096844

ABSTRACT

Here we show using mass photometry how proline substitutions, commonly used for SARS-CoV-2 spike stabilisation in vaccine design, directly affects ACE2 receptor interactions via dynamics of open and closed states. Conformational changes and ACE2 binding were influenced by spike variant and temperature, but independent of site-specific N-glycosylation.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Angiotensin-Converting Enzyme 2 , Spike Glycoprotein, Coronavirus/chemistry , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/chemistry , Receptors, Virus/metabolism , Protein Binding , Photometry , Molecular Dynamics Simulation , Binding Sites
13.
Sci Rep ; 12(1): 18168, 2022 Oct 28.
Article in English | MEDLINE | ID: covidwho-2096749

ABSTRACT

SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in the airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments have not been fully characterized using matched samples from large cohorts. Gene expression data from 793 nasal and 1673 bronchial brushes obtained from individuals participating in lung cancer screening or diagnostic workup revealed that smoking status (current versus former) was the only clinical factor significantly and reproducibly associated with VE gene expression. The expression of ACE2 and TMPRSS2 was higher in smokers in the bronchus but not in the nose. scRNA-seq of nasal brushings indicated that ACE2 co-expressed genes were highly expressed in club and C15orf48+ secretory cells while TMPRSS2 co-expressed genes were highly expressed in keratinizing epithelial cells. In contrast, these ACE2 and TMPRSS2 modules were highly expressed in goblet cells in scRNA-seq from bronchial brushings. Cell-type deconvolution of the gene expression data confirmed that smoking increased the abundance of several secretory cell populations in the bronchus, but only goblet cells in the nose. The association of ACE2 and TMPRSS2 with smoking in the bronchus is due to their high expression in goblet cells which increase in abundance in current smoker airways. In contrast, in the nose, these genes are not predominantly expressed in cell populations modulated by smoking. In individuals with elevated lung cancer risk, smoking-induced VE gene expression changes in the nose likely have minimal impact on SARS-CoV-2 infection, but in the bronchus, smoking may lead to higher viral loads and more severe disease.


Subject(s)
COVID-19 , Lung Neoplasms , Humans , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Early Detection of Cancer , Peptidyl-Dipeptidase A/metabolism , Lung Neoplasms/metabolism , Bronchi/metabolism , Smoking/adverse effects , Smoking/genetics
14.
ACS Infect Dis ; 8(11): 2259-2270, 2022 Nov 11.
Article in English | MEDLINE | ID: covidwho-2096630

ABSTRACT

SARS-CoV-2, a coronavirus strain that started a worldwide pandemic in early 2020, attaches to human cells by binding its spike (S) glycoprotein to a host receptor protein angiotensin-converting enzyme 2 (ACE2). Blocking the interaction between the S protein and ACE2 has emerged as an important strategy for preventing viral infection. We systematically developed and optimized an AlphaLISA assay to investigate binding events between ACE2 and the ectodomain of the SARS-CoV-2 S protein (S-614G: residues 1-1208 with a D614G mutation). Using S-614G permits discovering potential allosteric inhibitors that stabilize the S protein in a conformation that impedes its access to ACE2. Over 30,000 small molecules were screened in a high-throughput format for activity against S-614G and ACE2 binding using the AlphaLISA assay. A viral entry assay was used to validate hits using lentiviral particles pseudotyped with the full-length S protein of the Wuhan-1 strain. Two compounds identified in the screen, oleic acid and suramin, blocked the attachment of S-614G to ACE2 and S protein-driven cell entry into Calu-3 and ACE2-overexpressing HEK293T cells. Oleic acid inhibits S-614G binding to ACE2 far more potently than to the receptor-binding domain (RBD, residues 319-541 of SARS-CoV-2 S), potentially indicating a noncompetitive mechanism. The results indicate that using the full-length ectodomain of the S protein can be important for identifying allosteric inhibitors of ACE2 binding. The approach reported here represents a rapidly adaptable format for discovering receptor-binding inhibitors to S-proteins of future coronavirus strains.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Oleic Acid , HEK293 Cells , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism
15.
ACS Appl Bio Mater ; 5(11): 5140-5147, 2022 Nov 21.
Article in English | MEDLINE | ID: covidwho-2096625

ABSTRACT

Severe acute respiratory syndrome coronavirus 2's (SARS-CoV-2) rapid global spread has posed a significant threat to human health, and similar outbreaks could occur in the future. Developing effective virus inactivation technologies is critical to preventing and overcoming pandemics. The infection of SARS-CoV-2 depends on the binding of the spike glycoprotein (S) receptor binding domain (RBD) to the host cellular surface receptor angiotensin-converting enzyme 2 (ACE2). If this interaction is disrupted, SARS-CoV-2 infection could be inhibited. Magnetic nanoparticle (MNP) dispersions exposed to an alternating magnetic field (AMF) possess the unique ability for magnetically mediated energy delivery (MagMED); this localized energy delivery and associated mechanical, chemical, and thermal effects are a possible technique for inactivating viruses. This study investigates the MNPs' effect on vesicular stomatitis virus pseudoparticles containing the SARS-CoV-2 S protein when exposed to AMF or a water bath (WB) with varying target steady-state temperatures (45, 50, and 55 °C) for different exposure times (5, 15, and 30 min). In comparison to WB exposures at the same temperatures, AMF exposures resulted in significantly greater inactivation in multiple cases. This is likely due to AMF-induced localized heating and rotation of MNPs. In brief, our findings demonstrate a potential strategy for combating the SARS-CoV-2 pandemic or future ones.


Subject(s)
COVID-19 , Magnetite Nanoparticles , Humans , SARS-CoV-2 , Magnetite Nanoparticles/therapeutic use , Peptidyl-Dipeptidase A/chemistry , Magnetic Fields
16.
Langmuir ; 38(45): 13972-13982, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2096623

ABSTRACT

The spread of coronavirus disease 2019 caused by SARS-CoV-2 and its variants has become a global health crisis. Although there were many attempts to use nanomaterials-based devices to fight against SARS-CoV-2, it still remains elusive as to how the nanomaterials interact with SARS-CoV-2 and affect its biofunctions. Here, taking the graphene nanosheet (GN) as the model nanomaterial, we investigate its interaction with the spike protein in both WT and Omicron by molecular simulations. In the closed state, the GN can insert into the region between the receptor binding domain (RBD) and the N-terminal domain (NTD) in both wild type (WT) and Omicron, which keeps the RBD in the down conformation. In the open state, the GN can hamper the binding of up RBD to ACE2 in WT, but it has little impact on up RBD and, even worse, stimulates the down-to-up transition of down RBDs in Omicron. Moreover, the GN can insert in the vicinity of the fusion peptide in both WT and Omicron and prevents the detachment of S1 from the whole spike protein. The present study reveals the effect of the SARS-CoV-2 variant on the nanomaterial-spike protein interaction, which informs prospective efforts to design functional nanomaterials against SARS-CoV-2.


Subject(s)
COVID-19 , Graphite , Humans , Angiotensin-Converting Enzyme 2 , Peptidyl-Dipeptidase A/metabolism , Prospective Studies , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Nanostructures
17.
J Agric Food Chem ; 70(45): 14403-14413, 2022 Nov 16.
Article in English | MEDLINE | ID: covidwho-2096615

ABSTRACT

COVID-19 is initiated by binding the SARS-CoV-2 spike protein to angiotensin-converting enzyme 2 (ACE2) on host cells. Food factors capable of suppressing the binding between the SARS-CoV-2 spike protein and ACE2 or reducing the ACE2 availability through ACE2 inhibitions may potentially reduce the risk of SARS-CoV-2 infection and COVID-19. In this study, the chemical compositions of clove water and ethanol extracts were investigated, along with their potentials in suppressing SARS-CoV-2 spike protein-ACE2 binding, reducing ACE2 availability, and scavenging free radicals. Thirty-four compounds were tentatively identified in the clove water and ethanol extracts, with six reported in clove for the first time. Clove water and ethanol extracts dose-dependently suppressed SARS-CoV-2 spike protein binding to ACE2 and inhibited ACE2 activity. The water extract had stronger inhibitory effects than the ethanol extract on a dry weight basis. The clove water extract also had more potent free radical scavenging activities against DPPH• and ABTS•+ (536.9 and 3525.06 µmol TE/g, respectively) than the ethanol extract (58.44 and 2298.01 µmol TE/g, respectively). In contrast, the ethanol extract had greater total phenolic content (TPC) and relative HO• scavenging capacity (HOSC) values (180.03 mg GAE/g and 2181.08 µmol TE/g, respectively) than the water extract (120.12 mg GAE/g and 1483.02 µmol TE/g, respectively). The present study demonstrated the potential of clove in reducing the risk of SARS-CoV-2 infection and COVID-19 development.


Subject(s)
COVID-19 , Syzygium , Humans , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2 , Syzygium/metabolism , SARS-CoV-2 , Peptidyl-Dipeptidase A/chemistry , Protein Binding , Binding Sites , Free Radicals , Water , Ethanol
18.
Gastroenterol Hepatol ; 43(8): 464-471, 2020 Oct.
Article in English, Spanish | MEDLINE | ID: covidwho-2095369

ABSTRACT

The SARS-CoV-2 pandemic is leading to high mortality and a global health crisis. The primary involvement is respiratory; however, the virus can also affect other organs, such as the gastrointestinal tract and liver. The most common symptoms are anorexia and diarrhea. In about half of the cases, viral RNA could be detected in the stool, which is another line of transmission and diagnosis. covid19 has a worse prognosis in patients with comorbidities, although there is not enough evidence in case of previous digestive diseases. Digestive endoscopies may give rise to aerosols, which make them techniques with a high risk of infection. Experts and scientific organizations worldwide have developed guidelines for preventive measures. The available evidence on gastrointestinal and hepatic involvement, the impact on patients with previous digestive diseases and operating guidelines for Endoscopy Units during the pandemic are reviewed.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/complications , Digestive System Diseases/etiology , Digestive System/virology , Pandemics , Pneumonia, Viral/complications , Aerosols , Angiotensin-Converting Enzyme 2 , Anorexia/etiology , Antiviral Agents/adverse effects , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Cohort Studies , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Diarrhea/etiology , Digestive System Diseases/virology , Endoscopy, Digestive System/adverse effects , Feces/virology , Humans , Immunosuppressive Agents/adverse effects , Intestines/chemistry , Intestines/virology , Liver Diseases/etiology , Multicenter Studies as Topic , Pandemics/prevention & control , Peptidyl-Dipeptidase A/analysis , Peptidyl-Dipeptidase A/physiology , Personal Protective Equipment , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Receptors, Virus/analysis , Receptors, Virus/physiology , Risk , SARS-CoV-2 , Universal Precautions
19.
Chem Biol Interact ; 368: 110244, 2022 Dec 01.
Article in English | MEDLINE | ID: covidwho-2095126

ABSTRACT

Interactions between the human angiotensin-converting enzyme 2 (ACE2) and the RBD region of the SARS-CoV-2 Spike protein are critical for virus entry into the host cell. The objective of this work was to identify some of the most relevant SARS-CoV-2 Spike variants that emerged during the pandemic and evaluate their binding affinity with human variants of ACE2 since some ACE2 variants can enhance or reduce the affinity of the interaction between the ACE2 and S proteins. However, no information has been sought to extrapolate to different variants of SARS-CoV-2. Therefore, to understand the impact on the affinity of the interaction between ACE2 protein variants and SARS-CoV-2 protein S variants, molecular docking was used in this study to predict the effects of five mutations of ACE2 when they interact with Alpha, Beta, Delta, Omicron variants and a hypothetical variant, which present mutations in the RBD region of the SARS-CoV-2 Spike protein. Our results suggest that these variants could alter the interaction of the Spike and the human ACE2 protein, losing or creating new inter-protein contacts, enhancing viral fitness by improving binding affinity, and leading to an increase in infectivity, virulence, and transmission. This investigation highlighted that the S19P mutation of ACE2 decreases the binding affinity between the ACE2 and Spike proteins in the presence of the Beta variant and the wild-type variant of SARS-CoV-2 isolated in Wuhan-2019. The R115Q mutation of ACE2 lowers the binding affinity of these two proteins in the presence of the Beta and Delta variants. Similarly, the K26R mutation lowers the affinity of the interaction between the ACE2 and Spike proteins in the presence of the Alpha variant. This decrease in binding affinity is probably due to the lack of interaction between some of the key residues of the interaction complex between the ACE2 protein and the RBD region of the SARS-CoV-2 Spike protein. Therefore, ACE2 mutations appear in the presence of these variants, they could suggest an intrinsic resistance to COVID-19 disease. On the other hand, our results suggested that the K26R, M332L, and K341R mutations of ACE2 expressively showed the affinity between the ACE2 and Spike proteins in the Alpha, Beta, and Delta variants. Consequently, these ACE2 mutations in the presence of the Alpha, Beta, and delta variants of SARS-CoV-2 could be more infectious and virulent in human cells compared to the SARS-CoV-2 isolated in Wuhan-2019 and it could have a negative prognosis of the disease. Finally, the Omicron variant in interaction with ACE2 WT, S19P, R115Q, M332L, and K341R mutations of ACE2 showed a significant decrease in binding affinity. This could be consistent that the Omicron variant causes less severe symptoms than previous variants. On the other hand, our results suggested Omicron in the complex with K26R, the binding affinity is increased between ACE2/RBD, which could indicate a negative prognosis of the disease in people with these allelic conditions.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Molecular Docking Simulation , Mutation , Peptidyl-Dipeptidase A/chemistry , Protein Binding , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/genetics , Viral Envelope Proteins/metabolism , Virulence/genetics
20.
Inflamm Res ; 71(10-11): 1159-1167, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2094581

ABSTRACT

INTRODUCTION: Fenofibrate is an agonist of peroxisome proliferator activated receptor alpha (PPAR-α), that possesses anti-inflammatory, antioxidant, and anti-thrombotic properties. Fenofibrate is effective against a variety of viral infections and different inflammatory disorders. Therefore, the aim of critical review was to overview the potential role of fenofibrate in the pathogenesis of SARS-CoV-2 and related complications. RESULTS: By destabilizing SARS-CoV-2 spike protein and preventing it from binding angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 entry, fenofibrate can reduce SARS-CoV-2 entry in human cells Fenofibrate also suppresses inflammatory signaling pathways, which decreases SARS-CoV-2 infection-related inflammatory alterations. In conclusion, fenofibrate anti-inflammatory, antioxidant, and antithrombotic capabilities may help to minimize the inflammatory and thrombotic consequences associated with SARSCoV-2 infection. Through attenuating the interaction between SARS-CoV-2 and ACE2, fenofibrate can directly reduce the risk of SARS-CoV-2 infection. CONCLUSIONS: As a result, fenofibrate could be a potential treatment approach for COVID-19 control.


Subject(s)
COVID-19 , Fenofibrate , Thrombosis , Humans , Angiotensin-Converting Enzyme 2 , COVID-19/drug therapy , SARS-CoV-2 , Fenofibrate/therapeutic use , Antioxidants/metabolism , Peptidyl-Dipeptidase A/metabolism , Protein Binding
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