Polysulfates Block SARS-CoV-2 Uptake through Electrostatic Interactions*.
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ABSTRACT:
SUBMITTER: Nie C
PROVIDER: S-EPMC8250366 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:COVID-19 is increasingly affecting human health and global economy. Understanding the fundamental mechanisms of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is highly demanded to develop treatments for COVID-19. SARS-CoV and SARS-CoV-2 share 92.06% identity in their N protein RBDs' sequences, which results in very similar structures. However, the SARS-CoV-2 is more easily to spread. Utilizing multi-scale computational approaches, this work studied the fundamental mechanisms of the nucleocapsid (N) proteins of SARS-CoV and SARS-CoV-2, including their stabilities and binding strengths with RNAs at different pH values. Electrostatic potential on the surfaces of N proteins show that both the N proteins of SARS-CoV and SARS-CoV-2 have dominantly positive potential to attract RNAs. The binding forces between SARS-CoV N protein and RNAs at different distances are similar to that of SARS-CoV-2, both in directions and magnitudes. The electric filed lines between N proteins and RNAs are also similar for both SARS-CoV and SARS-CoV-2. The folding energy and binding energy dependence on pH revealed that the best environment for N proteins to perform their functions with RNAs is the weak acidic environment.
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Project description: Not available
| S-BSST379 | biostudies-other
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 μM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.
| S-EPMC8092326 | biostudies-literature
Project description:A structural understanding of the mechanism by which antibodies bind SARS-CoV-2 at the atomic level is highly desirable as it can tell the development of more effective antibodies to treat Covid-19. Here, we use steered molecular dynamics (SMD) and coarse-grained simulations to estimate the binding affinity of the monoclonal antibodies CR3022 and 4A8 to the SARS-CoV-2 receptor-binding domain (RBD) and SARS-CoV-2 N-terminal domain (NTD). Consistent with experiments, our SMD and coarse-grained simulations both indicate that CR3022 has a higher affinity for SARS-CoV-2 RBD than 4A8 for the NTD, and the coarse-grained simulations indicate the former binds three times stronger to its respective epitope. This finding shows that CR3022 is a candidate for Covid-19 therapy and is likely a better choice than 4A8. Energetic decomposition of the interaction energies between these two complexes reveals that electrostatic interactions explain the difference in the observed binding affinity between the two complexes. This result could lead to a new approach for developing anti-Covid-19 antibodies in which good candidates must contain charged amino acids in the area of contact with the virus.
| S-EPMC8276604 | biostudies-literature
Project description:Mutations in the receptor binding domain (RBD) in SARS-CoV-2 are shown to enhance its replication, transmissibility, and binding to host cells. Recently, a new strain is reported in India that includes a mutation (T478K, and L452R) in the RBD, that is possibly increasing the infection rate. Here, using Molecular Mechanics (MM) and Monte Carlo (MC) sampling, we show that the double mutant variant of SARS-CoV-2 induced conformational change in ACE2-E37, which enhanced the electrostatic interactions by the formation of a salt-bridge with SARS-CoV-2-R403. In addition, we observed that the double mutated structure induced a significant change in the salt-bridge electrostatic interaction between RBD-T500 and ACE2-D355. Where that this interaction lost more than 70% of its value compared to its value in WT protein.
| S-EPMC8650763 | biostudies-literature
Project description:The 2019 coronavirus pandemic remains a major public health concern. Neutralizing antibodies (nAbs) represent a cutting-edge antiviral strategy. We focus here on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, and discuss current progress in antibody research against rampant SARS-CoV-2 infections. We provide a perspective on the mechanisms of SARS-CoV-2-derived nAbs, comparing these with existing SARS-CoV-derived antibodies. We offer insight into how these antibodies cross-react and cross-neutralize by analyzing available structures of spike (S) glycoprotein-antibody complexes. We also propose ways of adopting antibody-based strategies - such as cocktail antibody therapeutics against SARS-CoV-2 - to overcome the possible resistance of currently identified mutants and mitigate possible antibody-dependent enhancement (ADE) pathologies. This review provides a platform for the progression of antibody and vaccine design against SARS-CoV-2, and possibly against future coronavirus pandemics.
| S-EPMC7498231 | biostudies-literature
Project description:Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here we uncover a role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.
| S-SCDT-10_1038-S44318-024-00061-0 | biostudies-other
Project description:The inhalation of ambient SARS-CoV-2-containing bioaerosols leads to infection and pandemic airborne transmission in susceptible populations. Filter-based respirators effectively reduce exposure but complicate normal respiration through breathing zone pressure differentials; therefore, they are impractical for long-term use.ObjectivesWe tested the comparative effectiveness of a prototyped miniaturized electrostatic precipitator (mEP) on a filter-based respirator (N95) via the removal of viral bioaerosols from a simulated, inspired air stream. Methods: Each respirator was tested within a 16 L environmental chamber housed within a Class III biological safety cabinet within biosafety level 3 containment. SARS-CoV-2-containing bioaerosols were generated in the chamber, drawn by a vacuum through each respirator, and physical particle removal and viral genomic RNA were measured distal to the breathing zone of each device.Measurements and main resultsThe mEP respirator removed particles (96.5 ± 0.4%), approximating efficiencies of the N95 (96.9 ± 0.6%). The mEP respirator similarly decreased SARS-CoV-2 viral RNA (99.792%) when compared to N95 removal (99.942%), as a function of particle removal from the airstream distal to the breathing zone of each respirator.ConclusionsThe mEP respirator approximated the performance of a filter-based N95 respirator for particle removal and viral RNA as a constituent of the SARS-CoV-2 bioaerosols generated for this evaluation. In practice, the mEP respirator could provide equivalent protection from ambient infectious bioaerosols as the N95 respirator without undue pressure drop to the wearer, thereby facilitating its long-term use in an unobstructed breathing configuration.
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Project description:RNA viruses that replicate in the cytoplasm often disrupt nucleocytoplasmic transport to preferentially translate their own transcripts and prevent host antiviral responses. The Sarbecovirus accessory protein ORF6 has previously been shown to be a major inhibitor of interferon production in both severe acute respiratory syndrome coronavirus (SARS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show SARS-CoV-2-infected cells display an elevated level of nuclear mRNA accumulation compared to mock-infected cells. We demonstrate that ORF6 is responsible for this nuclear imprisonment of host mRNA, and using a cotransfected reporter assay, we show this nuclear retention of mRNA blocks expression of newly transcribed mRNAs. ORF6's nuclear entrapment of host mRNA is associated with its ability to copurify with the mRNA export factors, Rae1 and Nup98. These protein-protein interactions map to the C terminus of ORF6 and can be abolished by a single amino acid mutation in Met58. Overexpression of Rae1 restores reporter expression in the presence of SARS-CoV-2 ORF6. SARS-CoV ORF6 also interacts with Rae1 and Nup98. However, SARS-CoV-2 ORF6 more strongly copurifies with Rae1 and Nup98 and results in significantly reduced expression of reporter proteins compared to SARS-CoV ORF6, a potential mechanism for the delayed symptom onset and presymptomatic transmission uniquely associated with the SARS-CoV-2 pandemic. We also show that both SARS-CoV and SARS-CoV-2 ORF6 block nuclear import of a broad range of host proteins. Together, these data support a model in which ORF6 clogs the nuclear pore through its interactions with Rae1 and Nup98 to prevent both nuclear import and export, rendering host cells incapable of responding to SARS-CoV-2 infection.IMPORTANCE SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), is an RNA virus with a large genome that encodes multiple accessory proteins. While these accessory proteins are not required for growth in vitro, they can contribute to the pathogenicity of the virus. We demonstrate that SARS-CoV-2-infected cells accumulate poly(A) mRNA in the nucleus, which is attributed to the accessory protein ORF6. Nuclear entrapment of mRNA and reduced expression of newly transcribed reporter proteins are associated with ORF6's interactions with the mRNA export proteins Rae1 and Nup98. SARS-CoV ORF6 also shows the same interactions with Rae1 and Nup98. However, SARS-CoV-2 ORF6 more strongly represses reporter expression and copurifies with Rae1 and Nup98 compared to SARS-CoV ORF6. Both SARS-CoV ORF6 and SARS-CoV-2 ORF6 block nuclear import of a wide range of host factors through interactions with Rae1 and Nup98. Together, our results suggest ORF6's disruption of nucleocytoplasmic transport prevents infected cells from responding to the invading virus.
| S-EPMC8092196 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has developed into a global pandemic since its first outbreak in the winter of 2019. An extensive investigation of SARS-CoV-2 is critical for disease control. Various recombinant monoclonal antibodies of human origin that neutralize SARS-CoV-2 infection have been isolated from convalescent patients and will be applied as therapies and prophylaxis. However, the need for dedicated monoclonal antibodies suitable for molecular pathology research is not fully addressed. Here, we produced six mouse anti-SARS-CoV-2 spike monoclonal antibodies that not only exhibit robust performance in immunoassays including western blotting, ELISA, immunofluorescence, and immunoprecipitation, but also demonstrate neutralizing activity against SARS-CoV-2 infection to VeroE6/TMPRSS2 cells. Due to their mouse origin, our monoclonal antibodies are compatible with the experimental immunoassay setups commonly used in basic molecular biology research laboratories, providing a useful tool for future research. Furthermore, in the hope of applying the antibodies of clinical setting, we determined the variable regions of the antibodies and used them to produce recombinant human/mouse chimeric antibodies.
| S-EPMC7846482 | biostudies-literature