Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development

Background: At the onset of the 2020 year, Coronavirus disease (COVID-19) has become a pandemic and infected many people worldwide. Despite all efforts, no cure was found for this infection. Bioinformatics and medicinal chemistry have a potential role in the primary consideration of drugs to treat this infection. With virtual screening and molecular docking, some potent compounds and medications can be found and modified and then applied to treat disease in the next steps. Methods: By virtual screening method and PRYX software, some Food and Drug Administration (FDA) approved drugs and natural compounds have been docked with the SPIKE protein of SARS-CoV-2. Some more potent agents have been selected, and then new structures are designed with better affinity than them. After that, we searched for the molecules with a similar structure to designed compounds to find the most potent compound to our target. Results: Because of the study of structures and affinities, mulberrofuran G was the most potent compound in this study. The compound has interacted strongly with residues in the probably active site of SPIKE. Conclusion: Mulberrofuran G can be a treatment agent candidate for COVID-19 because of its good affinity to SPIKE of the virus and inhibition of virus-cell adhesion and entrance.

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Two mutations in the SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk

10.1101/2020.11.17.386714 ◽

2020 ◽

Cited By ~ 1

Author(s):

Georg Hahn ◽

Chloe M. Wu ◽

Sanghun Lee ◽

Julian Hecker ◽

Sharon M. Lutz ◽

...

Keyword(s):

Rna Polymerase ◽

Viral Entry ◽

Structural Changes ◽

Potential Method ◽

Host Cells ◽

Host Susceptibility ◽

Spike Protein ◽

Highly Pathogenic ◽

Polymerase Complex ◽

Therapeutic Development

SARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Whole-genome sequencing (WGS) of the virus with death in SARS-CoV-2 patients is one potential method of early identification of highly pathogenic strains to target for containment. We analyzed 7,548 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) and associated variants with reported patient's health status from COVID-19, i.e. deceased versus non-deceased. We probed each locus of the single stranded RNA of the SARS-CoV-2 virus for direct association with host/patient mortality using a logistic regression. In total, evaluating 29,891 loci of the viral genome for association with patient/host mortality, two loci, at 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 4.09e-09 and 4.41e-23, respectively). Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development. Identification of these highly significant associations, unlikely to occur by chance, may assist with COVID-19 early containment of strains that are potentially highly pathogenic.

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D614G Spike Variant Does Not Alter IgG, IgM, or IgA Spike Seroassay Performance

10.1101/2020.07.08.20147371 ◽

2020 ◽

Cited By ~ 4

Author(s):

Carleen Klumpp-Thomas ◽

Heather Kalish ◽

Jennifer Hicks ◽

Jennifer Mehalko ◽

Matthew Drew ◽

...

Keyword(s):

New York ◽

New York City ◽

York City ◽

Potential Role ◽

Spike Protein ◽

Immune Memory ◽

Disease Biology ◽

New Variant ◽

High Incidence

Emergence of a new variant of spike protein (D614G) with increased infectivity and transmissibility has prompted many to analyze the potential role of this variant in the SARS-CoV-2 pandemic. When a new variant emerges, there is a concern regarding whether an individual exposed to one variant of a virus will have cross-reactive immune memory to the second variant. Accordingly, we analyzed the serologic reactivity of D614 (original) and G614 variant spike proteins. We found that antibodies from a high-incidence population in New York City reacted both toward the original D614 spike and the G614 spike variant. These data suggest that patients who have been exposed to either SARS-CoV-2 variant have humoral immunity that can respond against both variants. This is an important finding both for SARS-CoV-2 disease biology and for potential antibody-based therapeutics.

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The spike protein of SARS-CoV — a target for vaccine and therapeutic development

Nature Reviews Microbiology ◽

10.1038/nrmicro2090 ◽

2009 ◽

Vol 7 (3) ◽

pp. 226-236 ◽

Cited By ~ 564

Author(s):

Lanying Du ◽

Yuxian He ◽

Yusen Zhou ◽

Shuwen Liu ◽

Bo-Jian Zheng ◽

...

Keyword(s):

Spike Protein ◽

Therapeutic Development

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Potential role of ACE2 in coronavirus disease 2019 (COVID-19) prevention and management

Journal of Translational Internal Medicine ◽

10.2478/jtim-2020-0003 ◽

2020 ◽

Vol 8 (1) ◽

pp. 9-19 ◽

Cited By ~ 22

Author(s):

Mengyuan Liu ◽

Ting Wang ◽

Yun Zhou ◽

Yutong Zhao ◽

Yan Zhang ◽

...

Keyword(s):

Angiotensin Ii ◽

Potential Role ◽

Human Monoclonal Antibody ◽

Harmful Effect ◽

Spike Protein ◽

Angiotensin Ii Receptor Blocker ◽

Ang Ii ◽

Angiotensin Ii Receptor ◽

Novel Coronavirus

AbstractCOVID-19 is the current public health threat all over the world. Unfortunately, there is no specific prevention and treatment strategy for this disease. We aim to explore the potential role of angiotensin-converting enzyme 2 (ACE2) in this regard through this literature review. As a crucial enzyme of renin-angiotensin-aldosterone system (RAAS), ACE2 not only mediates the virus entry but also affects the pathophysiological process of virus-induced acute lung injury (ALI), as well as other organs’ damage. As interaction of COVID-19 virus spike and ACE2 is essential for virus infection, COVID-19-specific vaccine based on spike protein, small molecule compound interrupting their interaction, human monoclonal antibody based on receptor-binding domain, and recombinant human ACE2 protein (rhuACE2) have aroused the interests of researchers. Meanwhile, ACE2 could catalyze angiotensin II (Ang II) to form angiotensin 1-7 (Ang 1-7), thus alleviates the harmful effect of Ang II and amplifies the protection effect of Ang1-7. ACE inhibitor and angiotensin II receptor blocker (ARB) have been shown to increase the level of expression of ACE2 and could be potential strategies in protecting lungs, heart, and kidneys. ACE2 plays a very important role in the pathogenesis and pathophysiology of COVID-19 infection. Strategies targeting ACE2 and its ligand, COVID-19 virus spike protein, may provide novel method in the prevention and management of novel coronavirus pneumonia.

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Variety of Spike Protein in COVID-19 Mutation: Stability, Effectiveness and Outbreak Rate as a Target for Vaccine and Therapeutic Development

Biointerface Research in Applied Chemistry ◽

10.33263/briac113.1001610026 ◽

2020 ◽

Vol 11 (3) ◽

pp. 10016-10026

Keyword(s):

Web Sites ◽

Nuclear Import ◽

Flat Surface ◽

Protein Structures ◽

Protein Sequences ◽

Spike Protein ◽

Conserved Domain ◽

Protein Receptors ◽

Therapeutic Development ◽

Β Sheet

The structure of β-coronavirus MERS-CoV S1-CTD demonstrated an interesting subject of how two structurally similar viral RBDs recognize different protein receptors. Same as SARS-CoV, the S1-CTD, MERS-CoV S1-CTD viruses also contains two subdomains, but, in contrast to the loop-dominated MERS-CoV, RBM contains a 4-stranded antiparallel β-sheet, showing a relatively flat surface to bind DPP4. The protein sequences were obtained from NCBI web sites, and the proteins of COVID-19, such as protein sequences, were applied for analyzing the conserved domain. Some proteins were also utilized for constructing 3-D structures via homology modeling. We also show that N-terminal deletions of alpha 2 that no longer block STAT1 nuclear import. Covid-19 spike protein structures, along with peptide-like inhibitor structure of the SARS-CoV-2 spike glycoprotein, including small-molecule inhibitors, have been simulated via Molecular dynamic and docking methods. Several genomes of various coronaviruses using BAST and MAFFT software have been evaluated, and a few genomes have been selected.

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Enhancing the Prefusion Conformational Stability of SARS-CoV-2 Spike Protein Through Structure-Guided Design

Frontiers in Immunology ◽

10.3389/fimmu.2021.660198 ◽

2021 ◽

Vol 12 ◽

Author(s):

Timothy P. Riley ◽

Hui-Ting Chou ◽

Ruozhen Hu ◽

Krzysztof P. Bzymek ◽

Ana R. Correia ◽

...

Keyword(s):

Global Economy ◽

Vaccine Development ◽

Conformational Stability ◽

Spike Protein ◽

Great Promise ◽

Binding Domains ◽

Therapeutic Development ◽

Universal Applicability ◽

The Impact

The worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented and the impact on public health and the global economy continues to be devastating. Although early therapies such as prophylactic antibodies and vaccines show great promise, there are concerns about the long-term efficacy and universal applicability of these therapies as the virus continues to mutate. Thus, protein-based immunogens that can quickly respond to viral changes remain of continued interest. The Spike protein, the main immunogen of this virus, displays a highly dynamic trimeric structure that presents a challenge for therapeutic development. Here, guided by the structure of the Spike trimer, we rationally design new Spike constructs that show a uniquely high stability profile while simultaneously remaining locked into the immunogen-desirable prefusion state. Furthermore, our approach emphasizes the relationship between the highly conserved S2 region and structurally dynamic Receptor Binding Domains (RBD) to enable vaccine development as well as the generation of antibodies able to resist viral mutation.

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Mutations in SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk

10.21203/rs.3.rs-95183/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Christoph Lange ◽

Georg Hahn ◽

Chloe Wu ◽

Sanghun Lee ◽

Julian Hecker ◽

...

Keyword(s):

Rna Polymerase ◽

Viral Entry ◽

Viral Genome ◽

Structural Changes ◽

Host Cells ◽

Spike Protein ◽

Polymerase Complex ◽

Genome Wide ◽

Therapeutic Development ◽

Host Mortality

Abstract SARS-CoV-2 mortality has been extensively studied in relationship to a patient's predisposition to the disease. However, how sequence variations in the SARS-CoV-2 genome affect mortality is not understood. To address this issue, we used a whole-genome sequencing (WGS) association study to directly link death of SARS-CoV-2 patients with sequence variation in the viral genome. Specifically, we analyzed 3,626 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) with reported patient’s health status from COVID-19, i.e. deceased versus non-deceased. In total, evaluating 28,492 loci of the viral genome for association with patient/host mortality, two loci, 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 1.24e-12, and 1.24e-26, respectively). Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development.

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Antigenic minimalism of SARS-CoV-2 is linked to surges in COVID-19 community transmission and vaccine breakthrough infections

10.1101/2021.05.23.21257668 ◽

2021 ◽

Author(s):

AJ Venkatakrishnan ◽

Praveen Anand ◽

Patrick Lenehan ◽

Pritha Ghosh ◽

Rohit Suratekar ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Spike Protein ◽

Evolutionary Strategy ◽

Whole Genome ◽

Breakthrough Infection ◽

Viral Genomes ◽

Therapeutic Development ◽

Community Transmission ◽

Viral Sequencing

The raging COVID-19 pandemic in India and reports of vaccine breakthrough infections globally have raised alarm mandating the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed over 1.3 million SARS-CoV-2 genomes from 178 countries and performed whole-genome viral sequencing from 53 COVID-19 patients, including 20 vaccine breakthrough infections. We identified 116 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a three-month window. Deletions in the Spike protein N-terminal domain (NTD) are highly enriched for these surge-associated mutations (Odds Ratio = 18.2, 95% CI: 7.53-48.7; p=1.465x10-18). In the recent COVID-19 surge in India, an NTD deletion (ΔF157/R158) increased over 10-fold in prevalence from February 2021 (1.1%) to April 2021 (15%). During the recent surge in Chile, an NTD deletion (Δ246-253) increased rapidly over 30-fold in prevalence from January 2021 (0.86%) to April 2021 (33%). Strikingly, these simultaneously emerging deletions associated with surges in different parts of the world both occur at an antigenic supersite that is targeted by neutralizing antibodies. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences and identified deletions within this NTD antigenic supersite in a patient with vaccine breakthrough infection (Δ156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of NTD deletions throughout the pandemic and their association with case surges and vaccine breakthrough infections point to antigenic minimalism as an emerging evolutionary strategy for SARS-CoV-2 to evade immune responses. This study highlights the urgent need to sequence viral genomes at a larger scale globally and to mandate that sequences are deposited with more granular and transparent clinical annotations to ensure that therapeutic development keeps pace with the evolution of SARS-CoV-2.

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