Novel antibody epitopes dominate the antigenicity of spike glycoprotein in SARS-CoV-2 compared to SARS-CoV

Tracking the evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through genomic surveillance programs is undoubtedly one of the key priorities in the current pandemic situation. Although the genome of SARS-CoV-2 acquires mutations at a slower rate compared with other RNA viruses, evolutionary pressures derived from the widespread circulation of SARS-CoV-2 in the human population have progressively favored the global emergence though natural selection of several variants of concern that carry multiple non-synonymous mutations in the spike glycoprotein. Such mutations are often placed in key sites within major antibody epitopes and may therefore confer resistance to neutralizing antibodies, leading to partial immune escape, or otherwise compensate minor infectivity deficits associated with other mutations. As previously shown by other authors, several emerging variants carry recurrent deletion regions (RDRs) that display a partial overlap with antibody epitopes located in the spike N-terminal domain. Comparatively, very little attention has been directed towards spike insertion mutations, which often go unnoticed due to the use of insertion-unaware bioinformatics analysis pipelines. This manuscript describe a single recurrent insertion region (RIR1) in the N-terminal domain of SARS-CoV-2 spike protein, characterized by the independent acquisition of 3-4 additional codons between Arg214 and Asp215 in different viral lineages. Even though RIR1 is unlikely to confer antibody escape, its progressive increase in frequency and its association with two distinct emerging lineages (A.2.5 and B.1.214.2) warrant further investigation concerning its effects on spike structure and viral infectivity.

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Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

Science ◽

10.1126/science.abf6950 ◽

2021 ◽

Vol 371 (6534) ◽

pp. 1139-1142 ◽

Cited By ~ 34

Author(s):

Kevin R. McCarthy ◽

Linda J. Rennick ◽

Sham Nambulli ◽

Lindsey R. Robinson-McCarthy ◽

William G. Bain ◽

...

Keyword(s):

Amino Acids ◽

Neutralizing Antibodies ◽

Rna Viruses ◽

Human Populations ◽

Spike Glycoprotein ◽

Immune Pressure ◽

Global Concern ◽

Antigenic Evolution ◽

Antibody Epitopes ◽

Recurrent Deletion

Zoonotic pandemics, such as that caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can follow the spillover of animal viruses into highly susceptible human populations. The descendants of these viruses have adapted to the human host and evolved to evade immune pressure. Coronaviruses acquire substitutions more slowly than other RNA viruses. In the spike glycoprotein, we found that recurrent deletions overcome this slow substitution rate. Deletion variants arise in diverse genetic and geographic backgrounds, transmit efficiently, and are present in novel lineages, including those of current global concern. They frequently occupy recurrent deletion regions (RDRs), which map to defined antibody epitopes. Deletions in RDRs confer resistance to neutralizing antibodies. By altering stretches of amino acids, deletions appear to accelerate SARS-CoV-2 antigenic evolution and may, more generally, drive adaptive evolution.

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Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity and Pathogenesis?

10.26434/chemrxiv.12091260.v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Angelo Spinello ◽

Andrea Saltalamacchia ◽

Alessandra Magistrato

Keyword(s):

Health Economic ◽

Global Health ◽

Receptor Binding ◽

Binding Motif ◽

Spike Glycoprotein ◽

High Affinity ◽

Global Pandemic ◽

Medical Countermeasures ◽

High Infectivity ◽

Human Receptor

<p>The latest outbreak of a new pathogenic coronavirus (SARS-CoV-2) is provoking a global health, economic and societal crisis. All-atom simulations enabled us to uncover the key molecular traits underlying the high affinity of SARS-CoV-2 spike glycoprotein towards its human receptor, providing a rationale to its high infectivity. Harnessing this knowledge can boost developing effective medical countermeasures to fight the current global pandemic.</p>

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Unique nCoV-2019 (COVID 19) spike glycoprotein processing by host protease: Analysis and Implication on infection

Current Proteomics ◽

10.2174/1570164617999200612115218 ◽

2020 ◽

Vol 17 ◽

Author(s):

Ajoy Basak ◽

Sarmistha Basak

Keyword(s):

World Health ◽

Spike Glycoprotein ◽

Binding Domains ◽

Corona Virus ◽

Global Pandemic ◽

High Infection ◽

Crucial Information ◽

Glycoprotein Processing ◽

Health Organization ◽

Host Reservoir

: The current global pandemic outbreak of a novel type of corona virus termed by World Health Organization as COVID-19 became an grave concern and worry to human health and world economy. Intense research efforts are now underway worldwide to combat and prevent the spread of this deadly disease. This zoonotic virus, a native to bat population is most likely transmitted to human via a host reservoir. Due to its close similarity to previously known SARS CoV (Severe Acute Respiratory Syndrome Corona Virus) of 2002 and related MERS CoV (Middle East Respiratory Syndrome Corona Virus) of 2012, it is also known as SARS CoV2. But unlike them it is far too infectious, virulent and lethal. Among its various proteins, the surface spike glycoprotein “S” has drawn significant attention because of its implication in viral recognition and host-virus fusion process. A detail comparative analysis of “S” proteins of SARS CoV (now called SARS CoV1), SARS CoV2 (COVID-19) and MERS CoV based on structure, sequence alignment, host cleavage sites, receptor binding domains, potential glycosylation and Cys-disulphide bridge locations has been performed. It revealed some key features and variations that may elucidate the high infection and virulence character of COVID-19. Moreover this crucial information may become useful in our quest for COVID-19 therapeutics and vaccines.

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Role of key point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666200804161650 ◽

2020 ◽

Vol 20 ◽

Author(s):

Bipin Singh

Keyword(s):

Receptor Binding ◽

Point Mutations ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2 ◽

Recent Outbreak ◽

Novel Coronavirus ◽

Genomic Similarity

: The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its worldwide spread is posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARSCoV based on the comparison of the genome sequence. Despite the genomic similarity between SARS-CoV-2 and SARSCoV, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows the considerable difference compared to SARS-CoV, due to the presence of several point mutations. The analysis of receptor binding domain (RBD) from recently published 3D structures of spike glycoprotein of SARS-CoV-2 (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)) highlights the contribution of a few key point mutations in RBD of spike glycoprotein and molecular basis of its efficient binding with human angiotensin-converting enzyme 2 (ACE2).

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Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor

The Journal of Physical Chemistry B ◽

10.1021/acs.jpcb.1c02048 ◽

2021 ◽

Author(s):

Elhan Taka ◽

Sema Z. Yilmaz ◽

Mert Golcuk ◽

Ceren Kilinc ◽

Umut Aktas ◽

...

Keyword(s):

Spike Glycoprotein

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Tracking the interaction between single-wall carbon nanotube and SARS-Cov-2 spike glycoprotein: A molecular dynamics simulations study

Computers in Biology and Medicine ◽

10.1016/j.compbiomed.2021.104692 ◽

2021 ◽

pp. 104692

Author(s):

Masoumeh Jomhori Baloch ◽

Hamid Mosaddeghi ◽

Hamidreza Farzin

Keyword(s):

Molecular Dynamics ◽

Carbon Nanotube ◽

Molecular Dynamics Simulations ◽

Spike Glycoprotein ◽

Single Wall Carbon Nanotube ◽

Single Wall Carbon ◽

Dynamics Simulations

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Identification of Novel Neutralizing Monoclonal Antibodies against SARS-CoV-2 Spike Glycoprotein

ACS Pharmacology & Translational Science ◽

10.1021/acsptsci.1c00058 ◽

2021 ◽

Author(s):

Devivasha Bordoloi ◽

Ziyang Xu ◽

Michelle Ho ◽

Mansi Purwar ◽

Pratik Bhojnagarwala ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Spike Glycoprotein

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The Functional Consequences of the Novel Ribosomal Pausing Site in SARS-CoV-2 Spike Glycoprotein RNA

International Journal of Molecular Sciences ◽

10.3390/ijms22126490 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6490

Author(s):

Olga A. Postnikova ◽

Sheetal Uppal ◽

Weiliang Huang ◽

Maureen A. Kane ◽

Rafael Villasmil ◽

...

Keyword(s):

Amino Acid ◽

Insertion Sequence ◽

Experimental Studies ◽

Spike Protein ◽

Spike Glycoprotein ◽

Furin Cleavage ◽

New Host ◽

S Protein ◽

Furin Cleavage Site ◽

Ribosome Pausing

The SARS-CoV-2 Spike glycoprotein (S protein) acquired a unique new 4 amino acid -PRRA- insertion sequence at amino acid residues (aa) 681–684 that forms a new furin cleavage site in S protein as well as several new glycosylation sites. We studied various statistical properties of the -PRRA- insertion at the RNA level (CCUCGGCGGGCA). The nucleotide composition and codon usage of this sequence are different from the rest of the SARS-CoV-2 genome. One of such features is two tandem CGG codons, although the CGG codon is the rarest codon in the SARS-CoV-2 genome. This suggests that the insertion sequence could cause ribosome pausing as the result of these rare codons. Due to population variants, the Nextstrain divergence measure of the CCU codon is extremely large. We cannot exclude that this divergence might affect host immune responses/effectiveness of SARS-CoV-2 vaccines, possibilities awaiting further investigation. Our experimental studies show that the expression level of original RNA sequence “wildtype” spike protein is much lower than for codon-optimized spike protein in all studied cell lines. Interestingly, the original spike sequence produces a higher titer of pseudoviral particles and a higher level of infection. Further mutagenesis experiments suggest that this dual-effect insert, comprised of a combination of overlapping translation pausing and furin sites, has allowed SARS-CoV-2 to infect its new host (human) more readily. This underlines the importance of ribosome pausing to allow efficient regulation of protein expression and also of cotranslational subdomain folding.

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Immunogenicity of HIV-1-Based Virus-Like Particles with Increased Incorporation and Stability of Membrane-Bound Env

Vaccines ◽

10.3390/vaccines9030239 ◽

2021 ◽

Vol 9 (3) ◽

pp. 239

Author(s):

Christopher A. Gonelli ◽

Hannah A. D. King ◽

Charlene Mackenzie ◽

Secondo Sonza ◽

Rob J. Center ◽

...

Keyword(s):

Neutralizing Antibody ◽

Antibody Responses ◽

Neutralization Activity ◽

Virus Like Particles ◽

Antibody Isotypes ◽

Immunodeficiency Virus ◽

Proline Substitution ◽

Membrane Bound ◽

Antibody Epitopes ◽

Hiv 1

An optimal prophylactic vaccine to prevent human immunodeficiency virus (HIV-1) transmission should elicit protective antibody responses against the HIV-1 envelope glycoprotein (Env). Replication-incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present virion-associated Env with a native-like structure during vaccination that closely resembles that encountered on infectious virus. Here, we optimized the incorporation of Env into previously designed mature-form VLPs (mVLPs) and assessed their immunogenicity in mice. The incorporation of Env into mVLPs was increased by replacing the Env transmembrane and cytoplasmic tail domains with those of influenza haemagglutinin (HA-TMCT). Furthermore, Env was stabilized on the VLP surface by introducing an interchain disulfide and proline substitution (SOSIP) mutations typically employed to stabilize soluble Env trimers. The resulting mVLPs efficiently presented neutralizing antibody epitopes while minimizing exposure of non-neutralizing antibody sites. Vaccination of mice with mVLPs elicited a broader range of Env-specific antibody isotypes than Env presented on immature VLPs or extracellular vesicles. The mVLPs bearing HA-TMCT-modified Env consistently induced anti-Env antibody responses that mediated modest neutralization activity. These mVLPs are potentially useful immunogens for eliciting neutralizing antibody responses that target native Env epitopes on infectious HIV-1 virions.

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