Structure-Based Epitope Design: Toward a Greater Antibody–SARS-CoV-2 RBD Affinity (original) (raw)
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Journal of Biomolecular Structure and Dynamics, 2021
SARS-CoV-2, the causative agent behind the ongoing pandemic exhibits an enhanced potential for infection when compared to its related family members-the SARS-CoV and MERS-CoV; which have caused similar disease outbreaks in the past. The severity of the global health burden, increasing mortality rate and the emergent economic crisis urgently demands the development of next generation vaccines. Amongst such emergent next generation vaccines are the multi-epitope subunit vaccines, which hold promise in combating deadly pathogens. In this study we have exploited immunoinformatics applications to delineate a vaccine candidate possessing multiple B and T cells epitopes by utilizing the SARS-CoV-2 non structural and structural proteins. The antigenicity potential, safety, structural stability and the production feasibility of the designed construct was evaluated computationally. Furthermore, due to the known role of human TLR-3 immune receptor in viral sensing, which facilitates host cells activation for an immune response, the vaccine construct was examined for its binding efficiency using molecular docking and molecular dynamics simulation studies, which resulted in strong and stable interactions. Finally, the immune simulation studies suggested an effective immune response on vaccine administration. Overall, the immunoinformatics analysis advocates that the proposed vaccine candidate is safe and immunogenic and therefore can be pushed as a lead for in vitro and in vivo investigations.
Research Square (Research Square), 2020
Coronavirus disease-19 (COVID-19) is an acute resolved disease, with estimated 3.4% case fatality rate. Due to insufficient data and short onset time of the disease, researchers have to change the strategy against its associated virus, SARS-CoV-2. One of these strategies is the use of computational methods in the field of drug and vaccine design, which can greatly reduce the time and cost of the therapeutic or immunogenic development projects. In this study, we employed various immunoinformatics tools to design a multi-epitope vaccine polypeptide with the highest potential for activating the human immune system against SARS-CoV-2. The initial epitope set was extracted from the whole set of viral structural proteins. Their potential non-toxic and non-allergenic T-cell and B-cell binding and cytokine inducing epitopes were then identified through a priori immunoinformatic prediction. Selected epitopes were bonded to each other with appropriate links. A suitable adjuvant was added to the N-terminus of the vaccine polypeptide sequence to increase its immunogenicity. Molecular modelling of the 3D structure of the vaccine polypeptide, docking, molecular dynamics simulations and free energy calculations confirmed that the designed vaccine had high affinity for Toll-like receptor 3 binding, and that the vaccine-receptor complex was highly stable. Therefore, the designed polypeptide is promising for antigenicity and inducing an effective and safe immune response against SARS-CoV-2 inside the human body.
bioRxiv (Cold Spring Harbor Laboratory), 2022
As new variants of SARS-CoV-2 continue to emerge, it is important to assess the crossneutralizing capabilities of antibodies naturally elicited during wild type SARS-CoV-2 infection. In the present study, we evaluate the activity of nine anti-SARS-CoV-2 monoclonal antibodies (mAbs), previously isolated from convalescent donors infected with the Wuhan-Hu-1 strain, against the SARS-CoV-2 variants of concern (VOC) Alpha, Beta, Gamma, Delta and Omicron. By testing an array of mutated spike receptor binding domain (RBD) proteins, cell-expressed spike proteins from VOCs, and neutralization of SARS-CoV-2 VOCs as pseudoviruses, or as the authentic viruses in culture, we show that mAbs directed against the ACE2 binding site (ACE2bs) are more sensitive to viral evolution compared to anti-RBD non-ACE2bs mAbs, two of which retain their potency against all VOCs tested. At the second part of our study, we reveal the neutralization mechanisms at high molecular resolution of two anti-SARS-CoV-2 neutralizing mAbs by structural characterization. We solve the structures of the Delta-neutralizing ACE2bs mAb TAU-2303 with the SARS-CoV-2 spike trimer and RBD at 4.5 Å and 2.42 Å resolutions, respectively, revealing a similar mode of binding to that between the RBD and ACE2. Furthermore, we provide five additional structures (at resolutions of 4.7 Å, 7.3 Å, 6.4 Å, 3.3 Å, and 6.1 Å) of a second antibody, TAU-2212, complexed with the SARS-CoV-2 spike trimer. TAU-2212 binds an exclusively quaternary epitope, and exhibits a unique, flexible mode of neutralization that involves transitioning between five different conformations, with both arms of the antibody recruited for cross linking intra-and inter-spike RBD subunits. Our study provides additional mechanistic understanding about how antibodies neutralize SARS-CoV-2 and its emerging variants and provides insights on the likelihood of reinfections.
Expert Review of Vaccines, 2020
Introduction: The ongoing life-threatening pandemic of coronavirus disease 2019 (COVID-19) has extensively affected the world. During this global health crisis, it is fundamentally crucial to find strategies to combat SARS-CoV-2. Despite several efforts in this direction and continuing clinical trials, no vaccine has been approved for it yet. Methods: To find a preventive measure, we have computationally designed a multi-epitopic subunit vaccine using immuno-informatic approaches. Results: The structural proteins of SARS-CoV-2 involved in its survival and pathogenicity were used to predict antigenic epitopes. The antigenic epitopes were capable of eliciting a strong humoral as well as cellmediated immune response, our predictions suggest. The final vaccine was constructed by joining the all epitopes with specific linkers and to enhance their stability and immunogenicity. The physicochemical property of the vaccine was assessed. The vaccine 3D structure prediction and validation were done and docked with the human TLR-3 receptor. Furthermore, molecular dynamics simulations of the vaccine-TLR-3 receptor complex are employed to assess its dynamic motions and binding stability in-silico. Conclusion: Based on this study, we strongly suggest synthesizing this vaccine, which further can be tested in-vitro and in-vivo to check its potency in a cure for COVID-19.
Epitope profiling of coronavirus-binding antibodies using computational structural modelling
Identifying the epitope of an antibody is a key step in understanding its function and its potential as a therapeutic. It is well-established in the literature that sequence-based clonal clustering can identify antibodies with similar epitope complementarity. However, there is growing evidence that antibodies from markedly different lineages but with similar structures can engage the same epitope with near-identical binding modes. Here, we describe a novel computational method for epitope profiling based on structural modelling and clustering, and show how it can identify sequence-dissimilar antibodies that engage the same epitope. We start by searching for evidence of structural conservation across the latest solved SARS-CoV-2—binding antibody crystal structures. Despite the relatively small number of solved structures, we find numerous examples of sequence-diverse but structurally-similar coronavirus-binding antibodies engaging the same epitope. We therefore developed a high-throu...
In silico design of Multi-epitope-based peptide vaccine against SARS-CoV-2 using its spike protein
SARS-CoV-2 has been efficient in ensuring that many countries are brought to a standstill. With repercussions ranging from rampant mortality, fear, paranoia, and economic recession, the virus has brought together countries to look at possible therapeutic countermeasures. With prophylactic interventions possibly months away from being particularly effective, a slew of measures and possibilities concerning the design of vaccines are being worked upon. We attempted a structure-based approach utilizing a combination of epitope prediction servers and Molecular dynamic (MD) simulations to develop a multi-epitope-based subunit vaccine that involves the two subunits of the spike glycoprotein of SARS-CoV-2 (S1 and S2) coupled with a substantially effective chimeric adjuvant to create stable vaccine constructs. The designed constructs were evaluated based on their docking with Toll-Like Receptor (TLR) 4. Our findings provide an epitope-based peptide fragment that can be a potential candidate ...
Molecular Diversity, 2022
SARS, or severe acute respiratory syndrome, is caused by a novel coronavirus (COVID-19). This situation has compelled many pharmaceutical R&D companies and public health research sectors to focus their efforts on developing effective therapeutics. SARS-nCoV-2 was chosen as a protein spike to targeted monoclonal antibodies and therapeutics for prevention and treatment. Deep mutational scanning created a monoclonal antibody to characterize the effects of mutations in a variable antibody fragment based on its expression levels, specificity, stability, and affinity for specific antigenic conserved epitopes to the SpikeS Receptor Binding Domain (RBD). Improved contacts between Fv light and heavy chains and the targeted antigens of RBD could result in a highly potent neutralizing antibody (NAbs) response as well as cross-protection against other SARS-nCoV-2 strains. It undergoes multipoint core mutations that combine enhancing mutations, resulting in increased binding affinity and significantly increased stability between RBD and antibody. In addition, we improved. Structures of variable fragment (Fv) complexed with the RBD of Spike protein were subjected to our established in-silico antibody-engineering platform to obtain enhanced binding affinity to SARS-nCoV-2 and develop ability profiling. We found that the size and three-dimensional shape of epitopes significantly impacted the activity of antibodies produced against the RBD of Spike protein. Overall, because of the conformational changes between RBD and hACE2, it prevents viral entry. As a result of this in-silico study, the designed antibody can be used as a promising therapeutic strategy to treat COVID-19.
Design of multi-epitope vaccine candidate against SARS-CoV-2: a in-silico study
Journal of Biomolecular Structure and Dynamics, 2020
The best therapeutic strategy to find an effective vaccine against SARS-CoV-2 is to explore the target structural protein. In the present study, a novel multi-epitope vaccine is designed using in silico tools that potentially trigger both CD4 and CD8 T-cell immune responses against the novel Coronavirus. The vaccine candidate was designed using B and T-cell epitopes that can act as an immunogen and elicits immune response in the host system. NCBI was used for the retrieval of surface spike glycoprotein, of novel corona virus (SARS-CoV-2) strains. VaxiJen server screens the most important immunogen of all the proteins and IEDB server gives the prediction and analysis of B and T cell epitopes. Final vaccine construct was designed in silico composed of 425 amino acids including the 50S ribosomal protein adjuvant and the construct was computationally validated in terms of antigenicity, allergenicity and stability on considering all critical parameters into consideration. The results subjected to the modeling and docking studies of vaccine were validated. Molecular docking study revealed the protein-protein binding interactions between the vaccine construct and TLR-3 immune receptor. The MD simulations confirmed stability of the binding pose. The immune simulation results showed significant response for immune cells. The findings of the study confirmed that the final vaccine construct of chimeric peptide could able to enhance the immune response against nCoV-19.
PeerJ, 2021
Background The rapid Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV2) outbreak caused severe pandemic infection worldwide. The high mortality and morbidity rate of SARS CoV2 is due to the unavailability of vaccination and mutation in this virus. The present article aims to design a potential vaccine construct VTC3 targeting the non-mutational region of structural and non-structural proteins of SARS CoV2. Methods In this study, vaccines were designed using subtractive proteomics and reverse vaccinology. To target the virus adhesion and evasion, 10 different structural and non-structural proteins have been selected. Shortlisted proteins have been screened for B cell, T cell and IFN gamma interacting epitopes. 3D structure of vaccine construct was modeled and evaluated for its physicochemical properties, immunogenicity, allergenicity, toxicity and antigenicity. The finalized construct was implemented for docking and molecular dynamics simulation (MDS) with different toll-lik...
2021
Recently the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pervasive threat to public health so it is an emergency to vaccine development. The SARS-CoV-2 spike (S) glycoprotein plays a vital role in binds and fusion to the angiotensin-converting enzyme 2 (ACE2). The multi-epitope peptide vaccines are capable of inducing the specific humoral or cellular immune responses. In this regard, the RBD and spike cleavage site is the most probable target for vaccine development to inducing binds and fusion inhibitors neutralizing antibodies. In the present study, several immunoinformatics tools are used for analyzing the spike (S) glycoprotein sequence including the prediction of the potential linear B-cell epitopes, B-cell multi-epitope design, secondary and tertiary structures, physicochemical properties, solubility, antigenicity, and allergenicity for the promising vaccine candidate against SARS-CoV-2.