Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 360
Filter
Add filters

Document Type
Year range
1.
Viruses ; 13(12)2021 11 23.
Article in English | MEDLINE | ID: covidwho-1542792

ABSTRACT

The ongoing coronavirus disease (COVID-19) pandemic has required a variety of non-medical interventions to limit the transmission of the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One such option is over-the-counter nasal sprays that aim to block virus entry and transmission within the nasal cavity. In this study, we assessed the ability of three hydroxypropyl methylcellulose (HPMC)-based powder nasal sprays, produced by Nasaleze, to inhibit SARS-CoV-2 infection and release in vitro. Upon application, the HPMC powder forms a gel-like matrix within the nasal cavity-a process we recapitulated in cell culture. We found that virus release from cells previously infected with SARS-CoV-2 was inhibited by the gel matrix product in a dose-dependent manner, with virus levels reduced by >99.99% over a 72 h period at a dose of 6.4 mg/3.5 cm2. We also show that the pre-treatment of cells with product inhibited SARS-CoV-2 infection, independent of the virus variant. The primary mechanism of action appears to be via the formation of a physical, passive barrier. However, the addition of wild garlic provided additional direct antiviral properties in some formulations. We conclude that HPMC-based nasal sprays may offer an additional component to strategies to limit the spread of respiratory viruses, including SARS-CoV-2.


Subject(s)
COVID-19/prevention & control , Hypromellose Derivatives/pharmacology , SARS-CoV-2/drug effects , Animals , Chlorocebus aethiops , Dose-Response Relationship, Drug , Nasal Sprays , Vero Cells , Virus Internalization/drug effects , Virus Release/drug effects
2.
Phys Chem Chem Phys ; 23(27): 14873-14888, 2021 Jul 14.
Article in English | MEDLINE | ID: covidwho-1541260

ABSTRACT

The COVID-19 disease caused by the virus SARS-CoV-2, first detected in December 2019, is still emerging through virus mutations. Although almost under control in some countries due to effective vaccines that are mitigating the worldwide pandemic, the urgency to develop additional vaccines and therapeutic treatments is imperative. In this work, the natural polyphenols corilagin and 1,3,6-tri-O-galloy-ß-d-glucose (TGG) are investigated to determine the structural basis of inhibitor interactions as potential candidates to inhibit SARS-CoV-2 viral entry into target cells. First, the therapeutic potential of the ligands are assessed on the ACE2/wild-type RBD. We first use molecular docking followed by molecular dynamics, to take into account the conformational flexibility that plays a significant role in ligand binding and that cannot be captured using only docking, and then analyze more precisely the affinity of these ligands using MMPBSA binding free energy. We show that both ligands bind to the ACE2/wild-type RBD interface with good affinities which might prevent the ACE2/RBD association. Second, we confirm the potency of these ligands to block the ACE2/RBD association using a combination of surface plasmon resonance and biochemical inhibition assays. These experiments confirm that TGG and, to a lesser extent, corilagin, inhibit the binding of RBD to ACE2. Both experiments and simulations show that the ligands interact preferentially with RBD, while weak binding is observed with ACE2, hence, avoiding potential physiological side-effects induced by the inhibition of ACE2. In addition to the wild-type RBD, we also study numerically three RBD mutations (E484K, N501Y and E484K/N501Y) found in the main SARS-CoV-2 variants of concerns. We find that corilagin could be as effective for RBD/E484K but less effective for the RBD/N501Y and RBD/E484K-N501Y mutants, while TGG strongly binds at relevant locations to all three mutants, demonstrating the significant interest of these molecules as potential inhibitors for variants of SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , Gallic Acid/analogs & derivatives , Glucose/analogs & derivatives , Glucosides/chemistry , Hydrolyzable Tannins/chemistry , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , Gallic Acid/chemistry , Glucose/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Protein Binding/drug effects , Protein Interaction Domains and Motifs/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
3.
Sci Rep ; 11(1): 22195, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1514424

ABSTRACT

To initiate SARS-CoV-2 infection, the Receptor Binding Domain (RBD) on the viral spike protein must first bind to the host receptor ACE2 protein on pulmonary and other ACE2-expressing cells. We hypothesized that cardiac glycoside drugs might block the binding reaction between ACE2 and the Spike (S) protein, and thus block viral penetration into target cells. To test this hypothesis we developed a biochemical assay for ACE2:Spike binding, and tested cardiac glycosides as inhibitors of binding. Here we report that ouabain, digitoxin, and digoxin, as well as sugar-free derivatives digitoxigenin and digoxigenin, are high-affinity competitive inhibitors of ACE2 binding to the Original [D614] S1 and the α/ß/γ [D614G] S1 proteins. These drugs also inhibit ACE2 binding to the Original RBD, as well as to RBD proteins containing the ß [E484K], Mink [Y453F] and α/ß/γ [N501Y] mutations. As hypothesized, we also found that ouabain, digitoxin and digoxin blocked penetration by SARS-CoV-2 Spike-pseudotyped virus into human lung cells, and infectivity by native SARS-CoV-2. These data indicate that cardiac glycosides may block viral penetration into the target cell by first inhibiting ACE2:RBD binding. Clinical concentrations of ouabain and digitoxin are relatively safe for short term use for subjects with normal hearts. It has therefore not escaped our attention that these common cardiac medications could be deployed worldwide as inexpensive repurposed drugs for anti-COVID-19 therapy.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Cardiotonic Agents/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , A549 Cells , Animals , COVID-19/metabolism , Chlorocebus aethiops , Digitoxin/pharmacology , Digoxin/pharmacology , Humans , Lung/drug effects , Lung/metabolism , Ouabain/pharmacology , Protein Binding/drug effects , SARS-CoV-2/physiology , Vero Cells
4.
Biosci Rep ; 41(10)2021 10 29.
Article in English | MEDLINE | ID: covidwho-1510636

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compounds that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2)) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to down-regulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused down-regulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell-based antiviral drug screening assay showed 30-60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggest that these two closely related compounds possess multimodal anti-COVID-19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Biology/methods , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/immunology , COVID-19/immunology , Cell Line, Tumor , Drug Evaluation, Preclinical/methods , HSP70 Heat-Shock Proteins/antagonists & inhibitors , Humans , Mitochondrial Proteins/antagonists & inhibitors , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , SARS-CoV-2/immunology , Serine Endopeptidases/immunology , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
5.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Article in English | MEDLINE | ID: covidwho-1493345

ABSTRACT

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.


Subject(s)
Benzothiazoles/pharmacology , COVID-19/drug therapy , Oligopeptides/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/genetics , Animals , Benzamidines/chemistry , Benzothiazoles/pharmacokinetics , COVID-19/genetics , COVID-19/virology , Cell Line , Drug Design , Epithelial Cells/drug effects , Epithelial Cells/virology , Esters/chemistry , Guanidines/chemistry , Humans , Lung/drug effects , Lung/virology , Mice , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Oligopeptides/pharmacokinetics , SARS-CoV-2/pathogenicity , Serine Endopeptidases/drug effects , Serine Endopeptidases/ultrastructure , Small Molecule Libraries/pharmacology , Substrate Specificity/drug effects , Virus Internalization/drug effects
7.
Molecules ; 26(21)2021 Oct 26.
Article in English | MEDLINE | ID: covidwho-1488676

ABSTRACT

A novel human coronavirus prompted considerable worry at the end of the year 2019. Now, it represents a significant global health and economic burden. The newly emerged coronavirus disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the primary reason for the COVID-19 global pandemic. According to recent global figures, COVID-19 has caused approximately 243.3 million illnesses and 4.9 million deaths. Several human cell receptors are involved in the virus identification of the host cells and entering them. Hence, understanding how the virus binds to host-cell receptors is crucial for developing antiviral treatments and vaccines. The current work aimed to determine the multiple host-cell receptors that bind with SARS-CoV-2 and other human coronaviruses for the purpose of cell entry. Extensive research is needed using neutralizing antibodies, natural chemicals, and therapeutic peptides to target those host-cell receptors in extremely susceptible individuals. More research is needed to map SARS-CoV-2 cell entry pathways in order to identify potential viral inhibitors.


Subject(s)
Coronavirus/metabolism , Host Microbial Interactions/physiology , Receptors, Coronavirus/metabolism , Antibodies, Neutralizing , Antiviral Agents/pharmacology , COVID-19 , Coronavirus/pathogenicity , Humans , Receptors, Coronavirus/physiology , Receptors, Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
8.
Int J Mol Sci ; 22(21)2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1488619

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 infection poses a serious threat to global public health and the economy. The enzymatic product of cholesterol 25-hydroxylase (CH25H), 25-Hydroxycholesterol (25-HC), was reported to have potent anti-SARS-CoV-2 activity. Here, we found that the combination of 25-HC with EK1 peptide, a pan-coronavirus (CoV) fusion inhibitor, showed a synergistic antiviral activity. We then used the method of 25-HC modification to design and synthesize a series of 25-HC-modified peptides and found that a 25-HC-modified EK1 peptide (EK1P4HC) was highly effective against infections caused by SARS-CoV-2, its variants of concern (VOCs), and other human CoVs, such as HCoV-OC43 and HCoV-229E. EK1P4HC could protect newborn mice from lethal HCoV-OC43 infection, suggesting that conjugation of 25-HC with a peptide-based viral inhibitor was a feasible and universal strategy to improve its antiviral activity.


Subject(s)
Antiviral Agents/pharmacology , Hydroxycholesterols/chemistry , Lipopeptides/chemistry , SARS-CoV-2/drug effects , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Body Weight/drug effects , COVID-19/drug therapy , COVID-19/virology , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/pathogenicity , Coronavirus Infections/drug therapy , Coronavirus Infections/mortality , Coronavirus Infections/virology , Coronavirus OC43, Human/drug effects , Coronavirus OC43, Human/pathogenicity , Disease Models, Animal , Drug Synergism , Humans , Hydroxycholesterols/pharmacology , Hydroxycholesterols/therapeutic use , Lipopeptides/pharmacology , Lipopeptides/therapeutic use , Mice , Mice, Inbred BALB C , Polyethylene Glycols/chemistry , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Survival Rate , Virus Internalization/drug effects
9.
Int J Mol Sci ; 22(21)2021 Oct 26.
Article in English | MEDLINE | ID: covidwho-1488607

ABSTRACT

Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.


Subject(s)
Estrogens/chemistry , Estrogens/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Biological Transport , COVID-19/drug therapy , COVID-19/metabolism , Disease Models, Animal , Estrogens/pharmacology , Glycosylation/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Male , Mice, Inbred C57BL , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Polysaccharides/chemistry , Polysaccharides/metabolism , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Tunicamycin/pharmacology
10.
J Virol ; 95(19): e0086121, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1486519

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral pathogen causing the coronavirus disease 2019 (COVID-19) global pandemic. No effective treatment for COVID-19 has been established yet. The serine protease transmembrane protease serine 2 (TMPRSS2) is essential for viral spread and pathogenicity by facilitating the entry of SARS-CoV-2 into host cells. The protease inhibitor camostat, an anticoagulant used in the clinic, has potential anti-inflammatory and antiviral activities against COVID-19. However, the potential mechanisms of viral resistance and antiviral activity of camostat are unclear. Herein, we demonstrate high inhibitory potencies of camostat for a panel of serine proteases, indicating that camostat is a broad-spectrum inhibitor of serine proteases. In addition, we determined the crystal structure of camostat in complex with a serine protease (uPA [urokinase-type plasminogen activator]), which reveals that camostat is inserted in the S1 pocket of uPA but is hydrolyzed by uPA, and the cleaved camostat covalently binds to Ser195. We also generated a homology model of the structure of the TMPRSS2 serine protease domain. The model shows that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2, subsequently preventing SARS-CoV-2 spread. IMPORTANCE Serine proteases are a large family of enzymes critical for multiple physiological processes and proven diagnostic and therapeutic targets in several clinical indications. The serine protease transmembrane protease serine 2 (TMPRSS2) was recently found to mediate SARS-CoV-2 entry into the host. Camostat mesylate (FOY 305), a serine protease inhibitor active against TMPRSS2 and used for the treatment of oral squamous cell carcinoma and chronic pancreatitis, inhibits SARS-CoV-2 infection of human lung cells. However, the direct inhibition mechanism of camostat mesylate for TMPRSS2 is unclear. Herein, we demonstrate that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2 as uPA, subsequently preventing SARS-CoV-2 spread.


Subject(s)
Antiviral Agents/pharmacology , Esters/pharmacology , Guanidines/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/chemistry , Serine Endopeptidases/pharmacology , Serine Proteases/pharmacology , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/prevention & control , Carcinoma, Squamous Cell , Esters/chemistry , Esters/metabolism , Guanidines/chemistry , Guanidines/metabolism , Humans , Molecular Dynamics Simulation , Mouth Neoplasms , Protein Domains , Sequence Alignment , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Serine Proteases/chemistry , Serine Proteases/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Virus Internalization/drug effects
11.
Science ; 371(6536): 1379-1382, 2021 03 26.
Article in English | MEDLINE | ID: covidwho-1476374

ABSTRACT

Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.


Subject(s)
COVID-19/transmission , Lipopeptides/administration & dosage , Membrane Fusion/drug effects , SARS-CoV-2/drug effects , Viral Fusion Protein Inhibitors/administration & dosage , Virus Internalization/drug effects , Administration, Intranasal , Animals , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Drug Design , Ferrets , Lipopeptides/chemistry , Lipopeptides/pharmacokinetics , Lipopeptides/pharmacology , Mice , Pre-Exposure Prophylaxis , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Tissue Distribution , Vero Cells , Viral Fusion Protein Inhibitors/chemistry , Viral Fusion Protein Inhibitors/pharmacokinetics , Viral Fusion Protein Inhibitors/pharmacology
12.
Int J Mol Sci ; 22(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1470888

ABSTRACT

The ongoing COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a globally leading public health concern over the past two years. Despite the development and administration of multiple vaccines, the mutation of newer strains and challenges to universal immunity has shifted the focus to the lack of efficacious drugs for therapeutic intervention for the disease. As with SARS-CoV, MERS-CoV, and other non-respiratory viruses, flavonoids present themselves as a promising therapeutic intervention given their success in silico, in vitro, in vivo, and more recently, in clinical studies. This review focuses on data from in vitro studies analyzing the effects of flavonoids on various key SARS-CoV-2 targets and presents an analysis of the structure-activity relationships for the same. From 27 primary papers, over 69 flavonoids were investigated for their activities against various SARS-CoV-2 targets, ranging from the promising 3C-like protease (3CLpro) to the less explored nucleocapsid (N) protein; the most promising were quercetin and myricetin derivatives, baicalein, baicalin, EGCG, and tannic acid. We further review promising in silico studies featuring activities of flavonoids against SARS-CoV-2 and list ongoing clinical studies involving the therapeutic potential of flavonoid-rich extracts in combination with synthetic drugs or other polyphenols and suggest prospects for the future of flavonoids against SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Flavonoids/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Coronavirus Nucleocapsid Proteins/antagonists & inhibitors , Coronavirus Nucleocapsid Proteins/metabolism , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/physiology , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/metabolism , Rhinovirus/drug effects , Rhinovirus/physiology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Virus Internalization/drug effects
13.
Carbohydr Polym ; 275: 118779, 2022 Jan 01.
Article in English | MEDLINE | ID: covidwho-1466086

ABSTRACT

Previous researches suggested that polysaccharides from brown algae had anti-virus activity. We hypothesized that nature polysaccharide from marine plants might have the effect on anti-SARS-CoV-2 activity. By high throughput screening to target 3CLpro enzyme using polysaccharides library, we discover a crude polysaccharide 375 from seaweed Ecklonia kurome blocked 3CLpro enzymatic activity and shows good anti-SARS-CoV-2 infection activity in cell. Further, we show that homogeneous polysaccharide 37502 from the 375 may bind to 3CLpro well and disturb spike protein binding to ACE2 receptor. The structure characterization uncovers that 37502 is alginate. These results imply that the bioactivities of 375 on SARS-CoV-2 may target multiple key molecules implicated in the virus infection and replication. The above results suggest that 375 may be a potential drug candidate against SARS-CoV-2.


Subject(s)
COVID-19 , Polysaccharides , Humans , Molecular Docking Simulation , Seaweed/chemistry , Virus Internalization/drug effects
14.
Molecules ; 26(20)2021 Oct 09.
Article in English | MEDLINE | ID: covidwho-1463773

ABSTRACT

Glycyrrhizic acid (GA), also known as glycyrrhizin, is a triterpene glycoside isolated from plants of Glycyrrhiza species (licorice). GA possesses a wide range of pharmacological and antiviral activities against enveloped viruses including severe acute respiratory syndrome (SARS) virus. Since the S protein (S) mediates SARS coronavirus 2 (SARS-CoV-2) cell attachment and cell entry, we assayed the GA effect on SARS-CoV-2 infection using an S protein-pseudotyped lentivirus (Lenti-S). GA treatment dose-dependently blocked Lenti-S infection. We showed that incubation of Lenti-S virus, but not the host cells with GA prior to the infection, reduced Lenti-S infection, indicating that GA targeted the virus for infection. Surface plasmon resonance measurement showed that GA interacted with a recombinant S protein and blocked S protein binding to host cells. Autodocking analysis revealed that the S protein has several GA-binding pockets including one at the interaction interface to the receptor angiotensin-converting enzyme 2 (ACE2) and another at the inner side of the receptor-binding domain (RBD) which might impact the close-to-open conformation change of the S protein required for ACE2 interaction. In addition to identifying GA antiviral activity against SARS-CoV-2, the study linked GA antiviral activity to its effect on virus cell binding.


Subject(s)
Glycyrrhizic Acid/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Glycyrrhizic Acid/metabolism , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Humans , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization/drug effects
15.
Int J Mol Sci ; 22(20)2021 Oct 11.
Article in English | MEDLINE | ID: covidwho-1463714

ABSTRACT

SARS-CoV-2 exploits the respiratory tract epithelium including lungs as the primary entry point and reaches other organs through hematogenous expansion, consequently causing multiorgan injury. Viral E protein interacts with cell junction-associated proteins PALS1 or ZO-1 to gain massive penetration by disrupting the inter-epithelial barrier. Conversely, receptor-mediated viral invasion ensures limited but targeted infections in multiple organs. The ACE2 receptor represents the major virion loading site by virtue of its wide tissue distribution as demonstrated in highly susceptible lung, intestine, and kidney. In brain, NRP1 mediates viral endocytosis in a similar manner to ACE2. Prominently, PDZ interaction involves the entire viral loading process either outside or inside the host cells, whereas E, ACE2, and NRP1 provide the PDZ binding motif required for interacting with PDZ domain-containing proteins PALS1, ZO-1, and NHERF1, respectively. Hijacking NHERF1 and ß-arrestin by virion loading may impair specific sensory GPCR signalosome assembling and cause disordered cellular responses such as loss of smell and taste. PDZ interaction enhances SARS-CoV-2 invasion by supporting viral receptor membrane residence, implying that the disruption of these interactions could diminish SARS-CoV-2 infections and be another therapeutic strategy against COVID-19 along with antibody therapy. GPCR-targeted drugs are likely to alleviate pathogenic symptoms-associated with SARS-CoV-2 infection.


Subject(s)
COVID-19/pathology , Receptors, G-Protein-Coupled/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Humans , PDZ Domains , Receptors, G-Protein-Coupled/chemistry , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Signal Transduction , Virus Internalization/drug effects
16.
Top Curr Chem (Cham) ; 379(6): 40, 2021 Oct 08.
Article in English | MEDLINE | ID: covidwho-1460532

ABSTRACT

The highly infectious disease COVID-19 is induced by SARS-coronavirus 2 (SARS-CoV-2), which has spread rapidly around the globe and was announced as a pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 binds to the host cell's angiotensin converting enzyme 2 (ACE2) receptor through the viral surface spike glycoprotein (S-protein). ACE2 is expressed in the oral mucosa and can therefore constitute an essential route for entry of SARS-CoV-2 into hosts through the tongue and lung epithelial cells. At present, no effective treatments for SARS-CoV-2 are yet in place. Blocking entry of the virus by inhibiting ACE2 is more advantageous than inhibiting the subsequent stages of the SARS-CoV-2 life cycle. Based on current published evidence, we have summarized the different in silico based studies and repurposing of anti-viral drugs to target ACE2, SARS-CoV-2 S-Protein: ACE2 and SARS-CoV-2 S-RBD: ACE2. This review will be useful to researchers looking to effectively recognize and deal with SARS-CoV-2, and in the development of repurposed ACE2 inhibitors against COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Drug Repositioning , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Internalization/drug effects , Animals , Humans
17.
Eur Rev Med Pharmacol Sci ; 25(18): 5843-5852, 2021 09.
Article in English | MEDLINE | ID: covidwho-1451042

ABSTRACT

OBJECTIVE: The pandemic of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly transmissible and pathogenic coronavirus, has been representing enormous threats to the world in almost all aspects. S protein recognizing and binding to angiotensin-converting enzyme-2 (ACE2) receptor is the key step of viral infection. This review summarized the structure of S protein, and the difference among members of the coronaviridae, especially the different sites between SARS-CoV-2 and SARS-CoV S protein sequences. We reconstructed the phylogenetic tree of 18 coronaviruses based on S protein, and detected the conserved motif. We had a further discussion on various promising antiviral compounds, drugs or approaches for treatment. Considering that various virus mutants are rampant around the world, we introduced some SARS-CoV-2 mutants, which are more contagious and spread fast. It indicates the limitations of wide spectrum therapeutic research. We wish the information provided by this review can be helpful to the global battle against SARS-CoV-2 infection.


Subject(s)
Phylogeny , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/therapeutic use , Humans , Mutation , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Virus Replication/drug effects
18.
Protein Sci ; 30(11): 2206-2220, 2021 11.
Article in English | MEDLINE | ID: covidwho-1437079

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a pathogenic coronavirus causing COVID-19 infection. The interaction between the SARS-CoV-2 spike protein and the human receptor angiotensin-converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide-thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID-19. However, the molecular-level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID-19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID-19 infection or reducing the severity of the disease.


Subject(s)
COVID-19 , Oxidative Stress/drug effects , SARS-CoV-2/metabolism , Severity of Illness Index , Virus Internalization/drug effects , Vitamin D/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/pathology , COVID-19/prevention & control , Humans , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism
19.
Nat Commun ; 12(1): 5553, 2021 09 21.
Article in English | MEDLINE | ID: covidwho-1434104

ABSTRACT

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic, responsible for over 170 million infections, and over 3.7 million deaths worldwide. Efforts to test, treat and vaccinate against this pathogen all benefit from an improved understanding of the basic biology of SARS-CoV-2. Both viral and cellular proteases play a crucial role in SARS-CoV-2 replication. Here, we study proteolytic cleavage of viral and cellular proteins in two cell line models of SARS-CoV-2 replication using mass spectrometry to identify protein neo-N-termini generated through protease activity. We identify previously unknown cleavage sites in multiple viral proteins, including major antigens S and N: the main targets for vaccine and antibody testing efforts. We discover significant increases in cellular cleavage events consistent with cleavage by SARS-CoV-2 main protease, and identify 14 potential high-confidence substrates of the main and papain-like proteases. We show that siRNA depletion of these cellular proteins inhibits SARS-CoV-2 replication, and that drugs targeting two of these proteins: the tyrosine kinase SRC and Ser/Thr kinase MYLK, show a dose-dependent reduction in SARS-CoV-2 titres. Overall, our study provides a powerful resource to understand proteolysis in the context of viral infection, and to inform the development of targeted strategies to inhibit SARS-CoV-2 and treat COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/metabolism , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , COVID-19/drug therapy , Cell Line , Dipeptides/pharmacology , Humans , Mutation , Myosin-Light-Chain Kinase/antagonists & inhibitors , Myosin-Light-Chain Kinase/genetics , Myosin-Light-Chain Kinase/metabolism , Proteolysis , Proteomics , RNA, Small Interfering/pharmacology , SARS-CoV-2/genetics , Viral Proteases/metabolism , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Internalization/drug effects , Virus Replication/drug effects , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/genetics , src-Family Kinases/metabolism
20.
J Med Virol ; 93(10): 5825-5832, 2021 10.
Article in English | MEDLINE | ID: covidwho-1432413

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has focused attention on the need to develop effective therapeutics against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and also against other pathogenic coronaviruses. In this study, we report on a kind of bisbenzylisoquinoline alkaloid, neferine, as a pan-coronavirus entry inhibitor. Neferine effectively protected HEK293/hACE2 and HuH7 cell lines from infection by different coronaviruses pseudovirus particles (SARS-CoV-2, SARS-CoV-2 [D614G, N501Y/D614G, 501Y.V1, 501Y.V2, 501Y.V3 variants], SARS-CoV, MERS-CoV) in vitro, with median effect concentration (EC50 ) of 0.13-0.41 µM. Neferine blocked host calcium channels, thus inhibiting Ca2+ -dependent membrane fusion and suppressing virus entry. This study provides experimental data to support the fact that neferine may be a promising lead for pan-coronaviruses therapeutic drug development.


Subject(s)
Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , Calcium/metabolism , SARS-CoV-2/drug effects , Virus Internalization/drug effects , COVID-19/virology , Cell Line , Coronavirus/drug effects , Coronavirus/physiology , HEK293 Cells , Humans , Isoquinolines/pharmacology , Phenols/pharmacology , SARS-CoV-2/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...