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1.
J Nat Prod ; 84(8): 2385-2389, 2021 08 27.
Article in English | MEDLINE | ID: covidwho-1634670

ABSTRACT

The ongoing COVID-19 global pandemic caused by SARS-CoV-2 inspires the development of effective inhibitors to block the SARS-CoV-2 spike-ACE2 interaction. A chemical investigation on the fruiting bodies of Phellinus pini led to the isolation of five aromatic cadinane sesquiterpenoids including four new ones, named piniterpenoids A-D (1-4), as well as three known lignans. Their structures were determined by extensive spectroscopic analysis including HRMS and 1D and 2D NMR. All of the aromatic cadinane sesquiterpenoids inhibited the SARS-CoV-2 spike-ACE2 interaction, with IC50 values ranging from 64.5 to 99.1 µM. A molecular docking study showed the disruption of the interaction of compound 1 via hydrogen interactions with Arg403, Asp405, and Arg408 of SARS-CoV-2 RBD and Arg393 and His34 residues of ACE2. These results suggested that aromatic cadinane sesquiterpenoids might be useful in developing agents for COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Fruiting Bodies, Fungal/chemistry , Phellinus/chemistry , Polycyclic Sesquiterpenes/chemistry , Polycyclic Sesquiterpenes/pharmacology , SARS-CoV-2/drug effects , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Humans , Hydrogen Bonding/drug effects , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Docking Simulation
2.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Article in English | MEDLINE | ID: covidwho-1626013

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in tremendous loss worldwide. Although viral spike (S) protein binding of angiotensin-converting enzyme 2 (ACE2) has been established, the functional consequences of the initial receptor binding and the stepwise fusion process are not clear. By utilizing a cell-cell fusion system, in complement with a pseudoviral infection model, we found that the spike engagement of ACE2 primed the generation of S2' fragments in target cells, a key proteolytic event coupled with spike-mediated membrane fusion. Mutagenesis of an S2' cleavage site at the arginine (R) 815, but not an S2 cleavage site at arginine 685, was sufficient to prevent subsequent syncytia formation and infection in a variety of cell lines and primary cells isolated from human ACE2 knock-in mice. The requirement for S2' cleavage at the R815 site was also broadly shared by other SARS-CoV-2 spike variants, such as the Alpha, Beta, and Delta variants of concern. Thus, our study highlights an essential role for host receptor engagement and the key residue of spike for proteolytic activation, and uncovers a targetable mechanism for host cell infection by SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Membrane Fusion , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Animals , COVID-19/virology , HEK293 Cells , Host-Pathogen Interactions , Humans , Mice , Protein Binding , Proteolysis , Virus Internalization
3.
BMC Infect Dis ; 22(1): 47, 2022 Jan 12.
Article in English | MEDLINE | ID: covidwho-1622215

ABSTRACT

BACKGROUND: COVID-19, caused by SARS-CoV-2 has become the most threatening issue to all populations around the world. It is, directly and indirectly, affecting all of us and thus, is an emerging topic dealt in global health. To avoid the infection, various studies have been done and are still ongoing. COVID-19 cases are reported all over the globe, and among the millions of cases, genetic similarity may be seen. The genetical common features seen within confirmed cases may help outline the tendency of infection and degree severity of the disease. Here, we reviewed multiple papers on SNPs related to SARS-CoV-2 infection and analyzed their results. METHODS: The PubMed databases were searched for papers discussing SNPs associated with SARS-CoV-2 infection and severity. Clinical studies with human patients and statistically showing the relevance of the SNP with virus infection were included. Quality Assessment of all papers was done with Newcastle Ottawa Scale. RESULTS: In the analysis, 21 full-text literature out of 2956 screened titles and abstracts, including 63,496 cases, were included. All were human-based clinical studies, some based on certain regions gathered patient data and some based on big databases obtained online. ACE2, TMPRSS2, and IFITM3 are the genes mentioned most frequently that are related to SARS-CoV-2 infection. 20 out of 21 studies mentioned one or more of those genes. The relevant genes according to SNPs were also analyzed. rs12252-C, rs143936283, rs2285666, rs41303171, and rs35803318 are the SNPs that were mentioned at least twice in two different studies. CONCLUSIONS: We found that ACE2, TMPRSS2, and IFITM3 are the major genes that are involved in SARS-CoV-2 infection. The mentioned SNPs were all related to one or more of the above-mentioned genes. There were discussions on certain SNPs that increased the infection and severity to certain groups more than the others. However, as there is limited follow-up and data due to a shortage of time history of the disease, studies may be limited.


Subject(s)
COVID-19 , Population Health , Angiotensin-Converting Enzyme 2/genetics , Humans , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , RNA-Binding Proteins , SARS-CoV-2 , Serine Endopeptidases/genetics
4.
Chem Biodivers ; 18(11): e2100674, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1615945

ABSTRACT

Chemical investigation on a Streptomyces sp. strain MS180069 isolated from a sediment sample collected from the South China Sea, yielded the new benzo[f]isoindole-dione alkaloid, bhimamycin J (1). The structure was determined by extensive spectroscopic analysis, including HRMS, 1D, 2D NMR, and X-ray diffraction techniques. A molecular docking study revealed 1 as a new molecular motif that binds with human angiotensin converting enzyme2 (ACE2), recently described as the cell surface receptor responsible for uptake of 2019-CoV-2. Using enzyme assays we confirm that 1 inhibits human ACE2 79.7 % at 25 µg/mL.


Subject(s)
Alkaloids/chemistry , Geologic Sediments/microbiology , Isoindoles/chemistry , Streptomyces/chemistry , Alkaloids/metabolism , Alkaloids/pharmacology , Alkaloids/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Fungi/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Isoindoles/isolation & purification , Isoindoles/metabolism , Isoindoles/pharmacology , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Docking Simulation , SARS-CoV-2/isolation & purification , Streptomyces/isolation & purification , Streptomyces/metabolism
6.
PLoS One ; 17(1): e0260897, 2022.
Article in English | MEDLINE | ID: covidwho-1613343

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. METHODS: We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. RESULTS: Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55-75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. CONCLUSION: This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.


Subject(s)
COVID-19/genetics , COVID-19/mortality , Membrane Glycoproteins/genetics , Receptors, Interleukin-1/genetics , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , Cohort Studies , Factor X/genetics , Factor X/metabolism , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Membrane Glycoproteins/metabolism , Middle Aged , Netherlands/epidemiology , Polymorphism, Single Nucleotide/genetics , Receptors, Interleukin-1/metabolism , Retrospective Studies , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Treatment Outcome
7.
Commun Biol ; 5(1): 1421, 2022 01 06.
Article in English | MEDLINE | ID: covidwho-1612213

ABSTRACT

As the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic continues to spread, several variants of the virus, with mutations distributed all over the viral genome, are emerging. While most of the variants present mutations having little to no effects at the phenotypic level, some of these variants are spreading at a rate that suggests they may present a selective advantage. In particular, these rapidly spreading variants present specific mutations on the spike protein. These observations call for an urgent need to characterize the effects of these variants' mutations on phenotype features like contagiousness and antigenicity. With this aim, we performed molecular dynamics simulations on a selected set of possible spike variants in order to assess the stabilizing effect of particular amino acid substitutions on the molecular complex. We specifically focused on the mutations that are both characteristic of the top three most worrying variants at the moment, i.e the English, South African, and Amazonian ones, and that occur at the molecular interface between SARS-CoV-2 spike protein and its human ACE2 receptor. We characterize these variants' effect in terms of (i) residue mobility, (ii) compactness, studying the network of interactions at the interface, and (iii) variation of shape complementarity via expanding the molecular surfaces in the Zernike basis. Overall, our analyses highlighted greater stability of the three variant complexes with respect to both the wild type and two negative control systems, especially for the English and Amazonian variants. In addition, in the three variants, we investigate the effects a not-yet observed mutation in position 501 could provoke on complex stability. We found that a phenylalanine mutation behaves similarly to the English variant and may cooperate in further increasing the stability of the South African one, hinting at the need for careful surveillance for the emergence of these mutations in the population. Ultimately, we show that the proposed observables describe key features for the stability of the ACE2-spike complex and can help to monitor further possible spike variants.


Subject(s)
Amino Acid Substitution , Angiotensin-Converting Enzyme 2/genetics , Mutation , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Molecular Dynamics Simulation , Protein Binding
8.
Biophys J ; 120(14): 2793-2804, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1607417

ABSTRACT

The ongoing coronavirus disease 19 (COVID-19) pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host-cell receptor angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate the RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the metastable, prefusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, molecular docking was employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex were analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Angiotensin-Converting Enzyme 2 , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
9.
Biophys J ; 120(14): 2785-2792, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1603521

ABSTRACT

The entry of the severe acute respiratory syndrome coronavirus 2 virus in human cells is mediated by the binding of its surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor. A 23-residue long helical segment (SBP1) at the binding interface of human ACE2 interacts with viral spike protein and therefore has generated considerable interest as a recognition element for virus detection. Unfortunately, emerging reports indicate that the affinity of SBP1 to the receptor-binding domain of the spike protein is much lower than that of the ACE2 receptor itself. Here, we examine the biophysical properties of SBP1 to reveal factors leading to its low affinity for the spike protein. Whereas SBP1 shows good solubility (solubility > 0.8 mM), circular dichroism spectroscopy shows that it is mostly disordered with some antiparallel ß-sheet content and no helicity. The helicity is substantial (>20%) only upon adding high concentrations (≥20% v/v) of 2,2,2-trifluoroethanol, a helix promoter. Fluorescence correlation spectroscopy and single-molecule photobleaching studies show that the peptide oligomerizes at concentrations >50 nM. We hypothesized that mutating the hydrophobic residues (F28, F32, and F40) of SBP1, which do not directly interact with the spike protein, to alanine would reduce peptide oligomerization without affecting its spike binding affinity. Whereas the mutant peptide (SBP1mod) shows substantially reduced oligomerization propensity, it does not show improved helicity. Our study shows that the failure of efforts, so far, to produce a short SBP1 mimic with a high affinity for the spike protein is not only due to the lack of helicity but is also due to the heretofore unrecognized problem of oligomerization.


Subject(s)
COVID-19 , Peptidyl-Dipeptidase A , Angiotensin-Converting Enzyme 2 , Humans , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
11.
J Extracell Vesicles ; 11(1): e12179, 2022 01.
Article in English | MEDLINE | ID: covidwho-1605805

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry is mediated by the interaction of the viral spike (S) protein with angiotensin-converting enzyme 2 (ACE2) on the host cell surface. Although a clinical trial testing soluble ACE2 (sACE2) for COVID-19 is currently ongoing, our understanding of the delivery of sACE2 via small extracellular vesicles (sEVs) is still rudimentary. With excellent biocompatibility allowing for the effective delivery of molecular cargos, sEVs are broadly studied as nanoscale protein carriers. In order to exploit the potential of sEVs, we design truncated CD9 scaffolds to display sACE2 on the sEV surface as a decoy receptor for the S protein of SARS-CoV-2. Moreover, to enhance the sACE2-S binding interaction, we employ sACE2 variants. sACE2-loaded sEVs exhibit typical sEVs characteristics and bind to the S protein. Furthermore, engineered sEVs inhibit the entry of wild-type (WT), the globally dominant D614G variant, Beta (K417N-E484K-N501Y) variant, and Delta (L452R-T478K-D614G) variant SARS-CoV-2 pseudovirus, and protect against authentic SARS-CoV-2 and Delta variant infection. Of note, sACE2 variants harbouring sEVs show superior antiviral efficacy than WT sACE2 loaded sEVs. Therapeutic efficacy of the engineered sEVs against SARS-CoV-2 challenge was confirmed using K18-hACE2 mice. The current findings provide opportunities for the development of new sEVs-based antiviral therapeutics.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , COVID-19/immunology , Extracellular Vesicles/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Female , HEK293 Cells , Humans , Mice , Protein Binding , Protein Interaction Domains and Motifs
12.
Int J Mol Med ; 49(2)2022 02.
Article in English | MEDLINE | ID: covidwho-1594678

ABSTRACT

The pathophysiology of coronavirus disease 2019 (COVID­19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a wide­repertoire of possible cell entry mediators that appear to co­localise in a cell­ and tissue­specific manner. The present study provides an overview of the 'canonical' SARS­CoV­2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin­1, expanding on the involvement of novel candidates, including glucose­regulated protein 78, basigin, kidney injury molecule­1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factor­α convertase) and Toll­like receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID­19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARS­CoV­2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID­19 warrants further investigation.


Subject(s)
COVID-19/metabolism , MicroRNAs/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/virology , /metabolism , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/genetics , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Virus/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Viral Tropism
13.
Biochemistry (Mosc) ; 86(7): 800-817, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1594970

ABSTRACT

COVID-19, a new human respiratory disease that has killed nearly 3 million people in a year since the start of the pandemic, is a global public health challenge. Its infectious agent, SARS-CoV-2, differs from other coronaviruses in a number of structural features that make this virus more pathogenic and transmissible. In this review, we discuss some important characteristics of the main SARS-CoV-2 surface antigen, the spike (S) protein, such as (i) ability of the receptor-binding domain (RBD) to switch between the "standing-up" position (open pre-fusion conformation) for receptor binding and the "lying-down" position (closed pre-fusion conformation) for immune system evasion; (ii) advantage of a high binding affinity of the RBD open conformation to the human angiotensin-converting enzyme 2 (ACE2) receptor for efficient cell entry; and (iii) S protein preliminary activation by the intracellular furin-like proteases for facilitation of the virus spreading across different cell types. We describe interactions between the S protein and cellular receptors, co-receptors, and antagonists, as well as a hypothetical mechanism of the homotrimeric spike structure destabilization that triggers the fusion of the viral envelope with the cell membrane at physiological pH and mediates the viral nucleocapsid entry into the cytoplasm. The transition of the S protein pre-fusion conformation to the post-fusion one on the surface of virions after their treatment with some reagents, such as ß-propiolactone, is essential, especially in relation to the vaccine production. We also compare the COVID-19 pathogenesis with that of severe outbreaks of "avian" influenza caused by the A/H5 and A/H7 highly pathogenic viruses and discuss the structural similarities between the SARS-CoV-2 S protein and hemagglutinins of those highly pathogenic strains. Finally, we touch on the prospective and currently used COVID-19 antiviral and anti-pathogenetic therapeutics, as well as recently approved conventional and innovative COVID-19 vaccines and their molecular and immunological features.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Pandemics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , COVID-19/genetics , COVID-19/metabolism , Humans , Influenza A virus/chemistry , Influenza A virus/genetics , Influenza A virus/metabolism , Influenza, Human/epidemiology , Influenza, Human/genetics , Influenza, Human/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
14.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Article in English | MEDLINE | ID: covidwho-1599544

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein, we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting enzyme 2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.


Subject(s)
COVID-19/immunology , COVID-19/transmission , SARS-CoV-2/immunology , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral , COVID-19/therapy , Cell Fusion , Chlorocebus aethiops , HEK293 Cells , Humans , Immunization, Passive , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
15.
Emerg Microbes Infect ; 11(1): 208-211, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1598042

ABSTRACT

We performed an annotation of 35 mutations in the spike protein of the SARS-CoV-2 Omicron variant. Our analysis of the mutations indicates that Omicron has gained prominent immune evasion and potential for enhanced transmissibility. Previous modeling study has revealed that continued evolution in both immune evasion and enhanced transmissibility by SARS-CoV-2 would compromise vaccines as tools for the pandemic control. To combat the future variants of SARS-CoV-2, the world needs novel antiviral drugs that are effective at curb viral spreading without introducing additional selective pressure towards resistant variants.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Drug Design/methods , Receptors, Virus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/transmission , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , Humans , Immune Evasion , Mutation , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
16.
In Vivo ; 36(1): 371-374, 2022.
Article in English | MEDLINE | ID: covidwho-1596471

ABSTRACT

BACKGROUND: The epipharynx, with its high expression of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry factors angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), is a primary target for SARS-CoV-2 replication in the early stage of Coronavirus Disease 19 (COVID-19). Epipharyngeal abrasive therapy (EAT) is a treatment for epipharyngitis in Japan which involves applying zinc chloride to the epipharyngeal mucosa. In this study, we evaluated the expression patterns of ACE2 and TMPRSS2 in tissue samples from patients before and after EAT. PATIENTS AND METHODS: The study subjects were seven patients that had not been treated with EAT and 11 patients that had. For immunohistochemical assessment of the epipharyngeal mucosa, the staining intensity of ACE2 and TMPRSS2 was described as an immunohistochemical score (IHC score). RESULTS: The IHC scores for ACE2 and TEMPRSS2 in the EAT-treated group were 3.40-fold and 1.81-fold lower, respectively, than those in the non-treated group (p=0.0208 and p=0.0244, respectively). CONCLUSION: EAT down-regulates the expression of SARS-CoV-2 entry factors ACE2 and TMPRSS2. Thus, EAT has potential as a novel COVID-19 preventative method.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Humans , Japan , Peptidyl-Dipeptidase A/genetics , Serine Endopeptidases , Virus Internalization
17.
J Am Soc Mass Spectrom ; 33(1): 181-188, 2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1596214

ABSTRACT

Affinity selection-mass spectrometry, which includes magnetic microbead affinity selection-screening (MagMASS), is ideal for the discovery of ligands in complex mixtures that bind to pharmacological targets. Therapeutic agents are needed to prevent or treat COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection of human cells by SARS-CoV-2 involves binding of the virus spike protein subunit 1 (S1) to the human cell receptor angiotensin converting enzyme-2 (ACE2). Like antibodies, small molecules have the potential to block the interaction of the viral S1 protein with human ACE2 and prevent SARS-CoV-2 infection. Therefore, a MagMASS assay was developed for the discovery of ligands to the S1 protein. Unlike previous MagMASS approaches, this new assay used robotics for 5-fold enhancement of throughput and sensitivity. The assay was validated using the SBP-1 peptide, which is identical to the ACE2 amino acid sequence recognized by the S1 protein, and then applied to the discovery of natural ligands from botanical extracts. Small molecule ligands to the S1 protein were discovered in extracts of the licorice species, Glycyrrhiza inflata. In particular, the licorice ligand licochalcone A was identified through dereplication and comparison with standards using HPLC with high-resolution tandem mass spectrometry.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery/methods , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Binding Sites/drug effects , COVID-19/metabolism , Chalcones/chemistry , Chalcones/pharmacology , Drug Evaluation, Preclinical/methods , Fabaceae/chemistry , Humans , Ligands , Mass Spectrometry/methods , Molecular Docking Simulation , Protein Binding/drug effects , SARS-CoV-2/metabolism
18.
Anal Chem ; 94(2): 1187-1194, 2022 01 18.
Article in English | MEDLINE | ID: covidwho-1593828

ABSTRACT

Avidity is an effective and frequent phenomenon employed by nature to achieve extremely high-affinity interactions. As more drug discovery efforts aim to disrupt protein-protein interactions, it is becoming increasingly common to encounter systems that utilize avidity effects and to study these systems using surface-based technologies, such as surface plasmon resonance (SPR) or biolayer interferometry. However, heterogeneity introduced from multivalent binding interactions complicates the analysis of the resulting sensorgram. A frequently applied practice is to fit the data based on a 1:1 binding model, and if the fit does not describe the data adequately, then the experimental setup is changed to favor a 1:1 binding interaction. This reductionistic approach is informative but not always biologically relevant. Therefore, we aimed to develop an SPR-based assay that would reduce the heterogeneity to enable the determination of the kinetic rate constants for multivalent binding interactions using the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human receptor angiotensin-converting enzyme 2 (ACE2) as a model system. We employed a combinatorial approach to generate a sensor surface that could distinguish between monovalent and multivalent interactions. Using advanced data analysis algorithms to analyze the resulting sensorgrams, we found that controlling the surface heterogeneity enabled the deconvolution of the avidity-induced affinity enhancement for the SARS-CoV-2 spike protein and ACE2 interaction.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Humans , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Surface Plasmon Resonance
19.
In Vivo ; 36(1): 13-29, 2022.
Article in English | MEDLINE | ID: covidwho-1593602

ABSTRACT

Chronic and acute respiratory diseases pose a major problem for public health worldwide due to the high morbidity and mortality rates, while treatment options remain mostly symptomatic. The renin-angiotensin system (RAS) plays an important role in lung tissue, regulating pulmonary circulation and blood pressure, but also contributing to normal pulmonary function and development. Angiotensin-converting enzyme (ACE) and its homologous angiotensin-converting enzyme 2 (ACE2) are considered to be amongst the main RAS regulators and are highly expressed in the pulmonary vascular endothelium. This review discusses the impact of ACE and ACE2 functional gene polymorphisms on seven major pulmonary diseases, in terms of predisposition, course, and outcome, revealing their potential utility as both genetic markers and biomarkers. The discussed conditions include chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), lung cancer and pulmonary sarcoidosis (PS), as well as SARS-CoV-2 viral infection and COVID-19 disease.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Peptidyl-Dipeptidase A , Humans , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic , Renin-Angiotensin System/genetics , SARS-CoV-2
20.
J Chem Inf Model ; 62(1): 129-141, 2022 01 10.
Article in English | MEDLINE | ID: covidwho-1593565

ABSTRACT

Binding of the SARS-CoV-2 S-glycoprotein to cell receptors is vital for the entry of the virus into cells and subsequent infection. ACE2 is the main cell receptor for SARS-CoV-2, which can attach to the C-terminal receptor-binding domain (RBD) of the SARS-CoV-2 S-glycoprotein. The GRP78 receptor plays an anchoring role, which attaches to the RBD and increases the chance of other RBDs binding to ACE2. Although high levels of reactive oxygen and nitrogen species (RONS) are produced during viral infections, it is not clear how they affect the RBD structure and its binding to ACE2 and GRP78. In this research, we apply molecular dynamics simulations to study the effect of oxidation of the highly reactive cysteine (Cys) amino acids of the RBD on its binding to ACE2 and GRP78. The interaction energy of both ACE2 and GRP78 with the whole RBD, as well as with the RBD main regions, is compared in both the native and oxidized RBDs. Our results show that the interaction energy between the oxidized RBD and ACE2 is strengthened by 155 kJ/mol, increasing the binding of the RBD to ACE2 after oxidation. In addition, the interaction energy between the RBD and GRP78 is slightly increased by 8 kJ/mol after oxidation, but this difference is not significant. Overall, these findings highlight the role of RONS in the binding of the SARS-CoV-2 S-glycoprotein to host cell receptors and suggest an alternative mechanism by which RONS could modulate the entrance of viral particles into the cells.


Subject(s)
Cysteine/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Humans , Reactive Nitrogen Species , Reactive Oxygen Species , Receptors, Virus/metabolism , SARS-CoV-2
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