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1.
Sci Rep ; 12(1): 5320, 2022 03 29.
Article in English | MEDLINE | ID: covidwho-1768843

ABSTRACT

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires treatments with rapid clinical translatability. Here we develop a multi-target and multi-ligand virtual screening method to identify FDA-approved drugs with potential activity against SARS-CoV-2 at traditional and understudied viral targets. 1,268 FDA-approved small molecule drugs were docked to 47 putative binding sites across 23 SARS-CoV-2 proteins. We compared drugs between binding sites and filtered out compounds that had no reported activity in an in vitro screen against SARS-CoV-2 infection of human liver (Huh-7) cells. This identified 17 "high-confidence", and 97 "medium-confidence" drug-site pairs. The "high-confidence" group was subjected to molecular dynamics simulations to yield six compounds with stable binding poses at their optimal target proteins. Three drugs-amprenavir, levomefolic acid, and calcipotriol-were predicted to bind to 3 different sites on the spike protein, domperidone to the Mac1 domain of the non-structural protein (Nsp) 3, avanafil to Nsp15, and nintedanib to the nucleocapsid protein involved in packaging the viral RNA. Our "two-way" virtual docking screen also provides a framework to prioritize drugs for testing in future emergencies requiring rapidly available clinical drugs and/or treating diseases where a moderate number of targets are known.


Subject(s)
COVID-19 , Coronavirus Papain-Like Proteases , Nucleocapsid Proteins , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Binding Sites , COVID-19/drug therapy , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Humans , Nucleocapsid Proteins/antagonists & inhibitors , RNA, Viral , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors
2.
Molecules ; 27(5)2022 Mar 07.
Article in English | MEDLINE | ID: covidwho-1732132

ABSTRACT

The COVID-19 pandemic has led to the search for new molecules with antiviral activity against SARS-CoV-2. The entry of the virus into the cell is one of the main targets for inhibiting SARS-CoV-2 infection. Natural products are an important source of new therapeutic alternatives against diseases. Pseudotyped viruses allow the study of SARS-CoV-2 viral entry inhibitors, and due to their simplicity, they allow the screening of a large number of antiviral candidates in Biosafety Level 2 facilities. We used pseudotyped HIV-1 with the D614G SARS-CoV-2 spike glycoprotein to test its ability to infect ACE2-expressing HEK 293T cells in the presence of diverse natural products, including 21 plant extracts, 7 essential oils, and 13 compounds from plants and fungi. The 50% cytotoxic concentration (CC50) was evaluated using the resazurin method. From these analyses, we determined the inhibitory activity of the extract of Stachytarpheta cayennensis, which had a half-maximal inhibitory concentration (IC50) of 91.65 µg/mL, a CC50 of 693.5 µg/mL, and a selectivity index (SI) of 7.57, indicating its potential use as an inhibitor of SARS-CoV-2 entry. Moreover, our work indicates the usefulness of the pseudotyped-virus system in the screening of SARS-CoV-2 entry inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/chemistry , Virus Internalization/drug effects , Actinobacteria/chemistry , Actinobacteria/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Biological Products/metabolism , Biological Products/pharmacology , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/virology , HEK293 Cells , High-Throughput Screening Assays/methods , Humans , Oils, Volatile/chemistry , Oils, Volatile/pharmacology , Oils, Volatile/therapeutic use , Plant Extracts/chemistry , Plant Extracts/metabolism , Plant Extracts/pharmacology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism
4.
ACS Appl Bio Mater ; 5(2): 483-491, 2022 02 21.
Article in English | MEDLINE | ID: covidwho-1701160

ABSTRACT

Interleukin-mediated deep cytokine storm, an aggressive inflammatory response to SARS-CoV-2 virus infection in COVID-19 patients, is correlated directly with lung injury, multi-organ failure, and poor prognosis of severe COVID-19 patients. Curcumin (CUR), a phenolic antioxidant compound obtained from turmeric (Curcuma longa L.), is well-known for its strong anti-inflammatory activity. However, its in vivo efficacy is constrained due to poor bioavailability. Herein, we report that CUR-encapsulated polysaccharide nanoparticles (CUR-PS-NPs) potently inhibit the release of cytokines, chemokines, and growth factors associated with damage of SARS-CoV-2 spike protein (CoV2-SP)-stimulated liver Huh7.5 and lung A549 epithelial cells. Treatment with CUR-PS-NPs effectively attenuated the interaction of ACE2 and CoV2-SP. The effects of CUR-PS-NPs were linked to reduced NF-κB/MAPK signaling which in turn decreased CoV2-SP-mediated phosphorylation of p38 MAPK, p42/44 MAPK, and p65/NF-κB as well as nuclear p65/NF-κB expression. The findings of the study strongly indicate that organic NPs of CUR can be used to control hyper-inflammatory responses and prevent lung and liver injuries associated with CoV2-SP-mediated cytokine storm.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Curcumin/pharmacology , Cytokine Release Syndrome/prevention & control , MAP Kinase Signaling System/drug effects , NF-kappa B/metabolism , Nanoparticles/chemistry , Signal Transduction/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents/pharmacokinetics , Cell Survival/drug effects , Chemokines/biosynthesis , Curcumin/chemistry , Curcumin/pharmacokinetics , Cytokines/biosynthesis , Humans , Intercellular Signaling Peptides and Proteins/biosynthesis , Phosphorylation , Spike Glycoprotein, Coronavirus/physiology
5.
Signal Transduct Target Ther ; 7(1): 44, 2022 02 09.
Article in English | MEDLINE | ID: covidwho-1683982

ABSTRACT

The wide transmission and host adaptation of SARS-CoV-2 have led to the rapid accumulation of mutations, posing significant challenges to the effectiveness of vaccines and therapeutic antibodies. Although several neutralizing antibodies were authorized for emergency clinical use, convalescent patients derived natural antibodies are vulnerable to SARS-CoV-2 Spike mutation. Here, we describe the screen of a panel of SARS-CoV-2 receptor-binding domain (RBD) targeted nanobodies (Nbs) from a synthetic library and the design of a biparatopic Nb, named Nb1-Nb2, with tight affinity and super-wide neutralization breadth against multiple SARS-CoV-2 variants of concern. Deep-mutational scanning experiments identify the potential binding epitopes of the Nbs on the RBD and demonstrate that biparatopic Nb1-Nb2 has a strong escape-resistant feature against more than 60 tested RBD amino acid substitutions. Using pseudovirion-based and trans-complementation SARS-CoV-2 tools, we determine that the Nb1-Nb2 broadly neutralizes multiple SARS-CoV-2 variants at sub-nanomolar levels, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Kappa (B.1.617.1), and Mu (B.1.621). Furthermore, a heavy-chain antibody is constructed by fusing the human IgG1 Fc to Nb1-Nb2 (designated as Nb1-Nb2-Fc) to improve its neutralization potency, yield, stability, and potential half-life extension. For the new Omicron variant (B.1.1.529) that harbors unprecedented multiple RBD mutations, Nb1-Nb2-Fc keeps a firm affinity (KD < 1.0 × 10-12 M) and strong neutralizing activity (IC50 = 1.46 nM for authentic Omicron virus). Together, we developed a tetravalent biparatopic human heavy-chain antibody with ultrapotent and broad-spectrum SARS-CoV-2 neutralization activity which highlights the potential clinical applications.


Subject(s)
Antibodies, Neutralizing/pharmacology , Antibodies, Viral/pharmacology , Immunoglobulin Fc Fragments/pharmacology , Recombinant Fusion Proteins/pharmacology , SARS-CoV-2/drug effects , Single-Domain Antibodies/pharmacology , Antibodies, Neutralizing/biosynthesis , Antibodies, Neutralizing/genetics , Antibodies, Viral/biosynthesis , Antibodies, Viral/genetics , Antibody Affinity , Enzyme-Linked Immunosorbent Assay , Epitopes/chemistry , Epitopes/immunology , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression , Humans , Immunoglobulin Fc Fragments/biosynthesis , Immunoglobulin Fc Fragments/genetics , Models, Molecular , Neutralization Tests , Protein Binding/drug effects , Protein Conformation , Protein Interaction Domains and Motifs , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/immunology , Single-Domain Antibodies/biosynthesis , Single-Domain Antibodies/genetics , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
6.
Phys Chem Chem Phys ; 24(7): 4305-4316, 2022 Feb 16.
Article in English | MEDLINE | ID: covidwho-1671658

ABSTRACT

While the COVID-19 pandemic continues to worsen, effective medicines that target the life cycle of SARS-CoV-2 are still under development. As more highly infective and dangerous variants of the coronavirus emerge, the protective power of vaccines will decrease or vanish. Thus, the development of drugs, which are free of drug resistance is direly needed. The aim of this study is to identify allosteric binding modulators from a large compound library to inhibit the binding between the Spike protein of the SARS-CoV-2 virus and human angiotensin-converting enzyme 2 (hACE2). The binding of the Spike protein to hACE2 is the first step of the infection of host cells by the coronavirus. We first built a compound library containing 77 448 antiviral compounds. Molecular docking was then conducted to preliminarily screen compounds which can potently bind to the Spike protein at two allosteric binding sites. Next, molecular dynamics simulations were performed to accurately calculate the binding affinity between the spike protein and an identified compound from docking screening and to investigate whether the compound can interfere with the binding between the Spike protein and hACE2. We successfully identified two possible drug binding sites on the Spike protein and discovered a series of antiviral compounds which can weaken the interaction between the Spike protein and hACE2 receptor through conformational changes of the key Spike residues at the Spike-hACE2 binding interface induced by the binding of the ligand at the allosteric binding site. We also applied our screening protocol to another compound library which consists of 3407 compounds for which the inhibitory activities of Spike/hACE2 binding were measured. Encouragingly, in vitro data supports that the identified compounds can inhibit the Spike-ACE2 binding. Thus, we developed a promising computational protocol to discover allosteric inhibitors of the binding of the Spike protein of SARS-CoV-2 to the hACE2 receptor, and several promising allosteric modulators were discovered.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , COVID-19 , Spike Glycoprotein, Coronavirus , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Pandemics , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors
7.
Signal Transduct Target Ther ; 7(1): 23, 2022 01 25.
Article in English | MEDLINE | ID: covidwho-1655541
8.
Bioorg Chem ; 119: 105574, 2022 02.
Article in English | MEDLINE | ID: covidwho-1654103

ABSTRACT

The COVID-19 pandemic caused by the SARS-CoV-2 virus has led to a major public health burden and has resulted in millions of deaths worldwide. As effective treatments are limited, there is a significant requirement for high-throughput, low resource methods for the discovery of novel antivirals. The SARS-CoV-2 spike protein plays a key role in viral entry and has been identified as a therapeutic target. Using the available spike crystal structure, we performed a virtual screen with a library of 527 209 natural compounds against the receptor binding domain of this protein. Top hits from this screen were subjected to a second, more comprehensive molecular docking experiment and filtered for favourable ADMET properties. The in vitro activity of 10 highly ranked compounds was assessed using a virus neutralisation assay designed to facilitate viral entry in a physiologically relevant manner via the plasma membrane route. Subsequently, four compounds ZINC02111387, ZINC02122196, SN00074072 and ZINC04090608 were identified to possess antiviral activity in the µM range. These findings validate the virtual screening method as a tool for identifying novel antivirals and provide a basis for future drug development against SARS-CoV-2.


Subject(s)
Biological Products/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Biological Products/toxicity , Computer Simulation , Drug Evaluation, Preclinical , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Neutralization Tests , Reproducibility of Results , SARS-CoV-2/drug effects , Virus Internalization/drug effects
9.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Article in English | MEDLINE | ID: covidwho-1650946

ABSTRACT

The development of small-molecules targeting different components of SARS-CoV-2 is a key strategy to complement antibody-based treatments and vaccination campaigns in managing the COVID-19 pandemic. Here, we show that two thiol-based chemical probes that act as reducing agents, P2119 and P2165, inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, the angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity to the reduction of key disulfides, specifically by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol-reducing moiety pointed directly toward Cys432. These collective findings establish the vulnerability of human coronaviruses to thiol-based chemical probes and lay the groundwork for developing compounds of this class, as a strategy to inhibit the SARS-CoV-2 infection by shifting the spike glycoprotein redox scaffold.


Subject(s)
Amino Alcohols/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/pharmacology , Phenyl Ethers/pharmacology , Receptors, Virus/chemistry , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Sulfhydryl Compounds/pharmacology , Allosteric Regulation , Amino Alcohols/chemistry , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Cell Line , Disulfides/antagonists & inhibitors , Disulfides/chemistry , Disulfides/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Nasal Mucosa/drug effects , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Oxidation-Reduction , Phenyl Ethers/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/genetics , Receptors, Virus/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Sulfhydryl Compounds/chemistry
10.
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
11.
Int J Mol Sci ; 23(2)2022 Jan 13.
Article in English | MEDLINE | ID: covidwho-1625319

ABSTRACT

A rational therapeutic strategy is urgently needed for combating SARS-CoV-2 infection. Viral infection initiates when the SARS-CoV-2 receptor-binding domain (RBD) binds to the ACE2 receptor, and thus, inhibiting RBD is a promising therapeutic for blocking viral entry. In this study, the structure of lead antiviral candidate binder (LCB1), which has three alpha-helices (H1, H2, and H3), is used as a template to design and simulate several miniprotein RBD inhibitors. LCB1 undergoes two modifications: structural modification by truncation of the H3 to reduce its size, followed by single and double amino acid substitutions to enhance its binding with RBD. We use molecular dynamics (MD) simulations supported by ab initio density functional theory (DFT) calculations. Complete binding profiles of all miniproteins with RBD have been determined. The MD investigations reveal that the H3 truncation results in a small inhibitor with a -1.5 kcal/mol tighter binding to RBD than original LCB1, while the best miniprotein with higher binding affinity involves D17R or E11V + D17R mutation. DFT calculations provide atomic-scale details on the role of hydrogen bonding and partial charge distribution in stabilizing the minibinder:RBD complex. This study provides insights into general principles for designing potential therapeutics for SARS-CoV-2.


Subject(s)
COVID-19/drug therapy , SARS-CoV-2/chemistry , Small Molecule Libraries/chemistry , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Substitution , Antiviral Agents/chemistry , Computational Biology , Molecular Dynamics Simulation , Protein Binding , Protein Domains , Protein Structure, Secondary , Virus Internalization
12.
Viruses ; 14(1)2021 12 31.
Article in English | MEDLINE | ID: covidwho-1580398

ABSTRACT

We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell-cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.


Subject(s)
Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Biological Availability , Cell Line , Cell Survival/drug effects , Coronavirus/classification , Coronavirus/drug effects , HIV Fusion Inhibitors/chemistry , HIV Fusion Inhibitors/pharmacokinetics , HIV Fusion Inhibitors/pharmacology , Humans , Protein Binding , Rats , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors
13.
J Biomol Struct Dyn ; 39(13): 4618-4632, 2021 08.
Article in English | MEDLINE | ID: covidwho-1575345

ABSTRACT

Cinnamon has been utilized to remedy a lot of afflictions of humans. Literary works illustrate that it possesses numerous biological activities. Our research study is intended to recognize the phyto-derived antiviral substances from Cinnamon against COVID-19 main protease enzyme and to understand the in silico molecular basis of its activity. In the present study, 48 isolates compounds from Cinnamon retrieved from the PubMed database, are subjected to docking analysis. Docking study was performed using Autodock vina and PyRx software. Afterwards, admetSAR, as well as DruLiTo servers, were used to investigate drug-likeness prophecy. Our study shows that the nine phytochemicals of Cinnamon are very likely against the main protease enzyme of COVID-19. Further MD simulations could identify Tenufolin (TEN) and Pavetannin C1 (PAV) as hit compounds. Utilizing contemporary strategies, these phyto-compounds from a natural origin might establish a reliable medication or support lead identification. Identified hit compounds can be further taken for in vitro and in vivo studies to examine their effectiveness versus COVID-19.


Subject(s)
Cinnamomum zeylanicum/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , COVID-19 , Computer Simulation , Humans , Molecular Docking Simulation , SARS-CoV-2/drug effects
14.
J Virol Methods ; 301: 114424, 2022 03.
Article in English | MEDLINE | ID: covidwho-1559141

ABSTRACT

The novel coronavirus disease has spread rapidly and caused sustained pressure on economic and medical resources to many countries. Vaccines and effective drugs are needed to fight against the epidemic. Traditional Chinese Medicine (TCM) plays an important and effective role in the treatment of COVID-19. Therefore, the active components of TCM are potential structural basis for the discovery of antiviral drugs. Through screening by molecular docking, Oleanolic acid, Tryptanthrin, Chrysophanol and Rhein were found to have better spike protein and ACE2 inhibitory activity, which could block the invasion and recognition of SARS-CoV-2 at the same time, should be investigated as antiviral candidates.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Glycoproteins/metabolism , Humans , Molecular Docking Simulation , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism
15.
J Am Chem Soc ; 143(51): 21541-21548, 2021 12 29.
Article in English | MEDLINE | ID: covidwho-1545583

ABSTRACT

New neutralizing agents against SARS-CoV-2 and associated mutant strains are urgently needed for the treatment and prophylaxis of COVID-19. Herein, we develop a spherical cocktail neutralizing aptamer-gold nanoparticle (SNAP) to block the interaction between the receptor-binding domain (RBD) of SARS-CoV-2 and host ACE2. With the multivalent aptamer assembly as well as the steric hindrance effect of the gold scaffold, SNAP exhibits exceptional binding affinity against the RBD with a dissociation constant of 3.90 pM and potent neutralization against authentic SARS-CoV-2 with a half-maximal inhibitory concentration of 142.80 fM, about 2 or 3 orders of magnitude lower than that of the reported neutralizing aptamers and antibodies. More importantly, the synergetic blocking strategy of multivalent multisite binding and steric hindrance ensures broad neutralizing activity of SNAP, almost completely blocking the infection of three mutant pseudoviruses. Overall, the SNAP strategy provides a new direction for the development of antivirus agents against SARS-CoV-2 and other emerging coronaviruses.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Metal Nanoparticles/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antibodies, Viral , Binding Sites , Gold , Humans , Mutation/drug effects
16.
Infect Genet Evol ; 97: 105153, 2022 01.
Article in English | MEDLINE | ID: covidwho-1521407

ABSTRACT

Amid the ongoing COVID-19 pandemic, it has become increasingly important to monitor the mutations that arise in the SARS-CoV-2 virus, to prepare public health strategies and guide the further development of vaccines and therapeutics. The spike (S) protein and the proteins comprising the RNA-Dependent RNA Polymerase (RdRP) are key vaccine and drug targets, respectively, making mutation surveillance of these proteins of great importance. Full protein sequences were downloaded from the GISAID database, aligned, and the variants identified. 437,006 unique viral genomes were analyzed. Polymorphisms in the protein sequence were investigated and examined longitudinally to identify sequence and strain variants appearing between January 5th, 2020 and January 16th, 2021. A structural analysis was also performed to investigate mutations in the receptor binding domain and the N-terminal domain of the spike protein. Within the spike protein, there were 766 unique mutations observed in the N-terminal domain and 360 in the receptor binding domain. Four residues that directly contact ACE2 were mutated in more than 100 sequences, including positions K417, Y453, S494, and N501. Within the furin cleavage site of the spike protein, a high degree of conservation was observed, but the P681H mutation was observed in 10.47% of sequences analyzed. Within the RNA dependent RNA polymerase complex proteins, 327 unique mutations were observed in Nsp8, 166 unique mutations were observed in Nsp7, and 1157 unique mutations were observed in Nsp12. Only 4 sequences analyzed contained mutations in the 9 residues that directly interact with the therapeutic Remdesivir, suggesting limited mutations in drug interacting residues. The identification of new variants emphasizes the need for further study on the effects of the mutations and the implications of increased prevalence, particularly for vaccine or therapeutic efficacy.


Subject(s)
COVID-19/epidemiology , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Genome, Viral , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Viral Nonstructural Proteins/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Africa/epidemiology , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacology , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Asia/epidemiology , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Coronavirus RNA-Dependent RNA Polymerase/genetics , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Databases, Factual , Epidemiological Monitoring , Europe/epidemiology , Evolution, Molecular , Furin/genetics , Furin/metabolism , Gene Expression , Humans , Molecular Docking Simulation , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/classification , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , United States/epidemiology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
17.
J Mol Model ; 27(11): 323, 2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1525539

ABSTRACT

The world has face the COVID-19 pandemic which has already caused millions of death. Due to the urgency in fighting the virus, we study five residues of free amino acids present in the structure of the SARS-CoV-2 spike protein (S). We investigated the spontaneous interaction between amino acids and silver ions (Ag+), considering these ions as a virucide chemical agent for SARS-CoV-2. The amino acid-Ag+ systems were investigated in a gaseous medium and a simulated water environment was described with a continuum model (PCM) the calculations were performed within the framework of density functional theory (DFT). Calculations related to the occupied orbitals of higher energy showed that Ag+ has a tendency to interact with the nitrile groups (-NH). The negative values of the Gibbs free energies show that the interaction process between amino acids-Ag+ in both media occurs spontaneously. There is a decrease in Gibbs free energy from the amino acid-Ag+ interactions immersed in a water solvation simulator.


Subject(s)
Amino Acids/chemistry , Antiviral Agents/chemistry , Density Functional Theory , Silver/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acids/metabolism , Antiviral Agents/metabolism , Binding Sites , Cations, Monovalent , Gene Expression , Humans , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , Silver/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Static Electricity , Thermodynamics
18.
Int J Mol Sci ; 22(22)2021 Nov 17.
Article in English | MEDLINE | ID: covidwho-1524024

ABSTRACT

The worldwide outbreak of COVID-19 was caused by a pathogenic virus called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Therapies against SARS-CoV-2 target the virus or human cells or the immune system. However, therapies based on specific antibodies, such as vaccines and monoclonal antibodies, may become inefficient enough when the virus changes its antigenicity due to mutations. Polyphenols are the major class of bioactive compounds in nature, exerting diverse health effects based on their direct antioxidant activity and their effects in the modulation of intracellular signaling. There are currently numerous clinical trials investigating the effects of polyphenols in prophylaxis and the treatment of COVID-19, from symptomatic, via moderate and severe COVID-19 treatment, to anti-fibrotic treatment in discharged COVID-19 patients. Antiviral activities of polyphenols and their impact on immune system modulation could serve as a solid basis for developing polyphenol-based natural approaches for preventing and treating COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/prevention & control , Polyphenols/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/metabolism , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/metabolism , Humans , Plants, Medicinal/chemistry , Plants, Medicinal/metabolism , Polyphenols/chemistry , Polyphenols/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism
19.
Molecules ; 26(22)2021 Nov 10.
Article in English | MEDLINE | ID: covidwho-1512512

ABSTRACT

The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19.


Subject(s)
COVID-19/drug therapy , Drug Repositioning , Phytochemicals/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Humans , Phytochemicals/chemistry , Phytochemicals/metabolism , Phytochemicals/pharmacology , Plants, Medicinal/chemistry , Plants, Medicinal/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
20.
Int J Mol Sci ; 22(22)2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1512386

ABSTRACT

Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by important respiratory impairments frequently associated with severe cardiovascular damages. Moreover, patients with pre-existing comorbidity for cardiovascular diseases (CVD) often present a dramatic increase in inflammatory cytokines release, which increases the severity and adverse outcomes of the infection and, finally, mortality risk. Despite this evident association at the clinical level, the mechanisms linking CVD and COVID-19 are still blurry and unresolved. Noncoding RNAs (ncRNAs) are functional RNA molecules transcribed from DNA but usually not translated into proteins. They play an important role in the regulation of gene expression, either in relatively stable conditions or as a response to different stimuli, including viral infection, and are therefore considered a possible important target in the design of specific drugs. In this review, we introduce known associations and interactions between COVID-19 and CVD, discussing the role of ncRNAs within SARS-CoV-2 infection from the perspective of the development of efficient pharmacological tools to treat COVID-19 patients and taking into account the equally dramatic associated consequences, such as those affecting the cardiovascular system.


Subject(s)
COVID-19/genetics , Cardiovascular Diseases/genetics , RNA, Untranslated/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Cardiovascular Diseases/pathology , Humans , RNA Interference , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology
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