Evolution of the SARS-CoV-2 Omicron spike

Cell Reports, Journal Year: 2023, Volume and Issue: 42(12), P. 113444 - 113444

Published: Nov. 18, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. spike (S) protein accumulated an unprecedented number sequence changes relative to previous variants. In this review, we discuss how S structural features modulate host cell receptor binding, virus entry, immune evasion highlight these differentiate from We also examine key properties track across the still-evolving subvariants importance continuing surveillance evolution over time.

Language: Английский

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AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants: Mutational Profiling of Binding Energetics Reveals Epistatic Drivers of the ACE2 Affinity and Escape Hotspots of Antibody Resistance

Viruses, Journal Year: 2024, Volume and Issue: 16(9), P. 1458 - 1458

Published: Sept. 13, 2024

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth fitness due to convergent evolution functional hotspots. These hotspots operate in tandem optimize both receptor binding for effective infection immune evasion efficiency, thereby maintaining overall fitness. lack molecular details on structure, dynamics energetics the latest FLiRT FLuQE with ACE2 antibodies provides a considerable challenge that is explored this study. We combined AlphaFold2-based atomistic predictions structures conformational ensembles spike complexes host dominant JN.1, KP.1, KP.2 KP.3 examine mechanisms underlying role balancing antibody evasion. Using ensemble-based mutational scanning protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions protect restore ACE2-binding affinity while conferring beneficial escape. To escape mechanisms, performed structure-based profiling several classes displayed impaired neutralization against BA.2.86, KP.3. confirmed experimental data harboring L455S F456L mutations can significantly impair neutralizing activity class 1 monoclonal antibodies, effects mediated by facilitate subsequent convergence Q493E changes rescue binding. Structural energetic analysis provided rationale showing BD55-5840 BD55-5514 bind different epitopes retain efficacy all examined support notion may favor emergence lineages combinations involving mediators control balance high

Language: Английский

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Full-spike deep mutational scanning helps predict the evolutionary success of SARS-CoV-2 clades

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 14, 2023

SARS-CoV-2 variants acquire mutations in spike that promote immune evasion and impact other properties contribute to viral fitness such as ACE2 receptor binding cell entry. Knowledge of how affect these phenotypes can provide insight into the current potential future evolution virus. Here we use pseudovirus deep mutational scanning measure >9,000 across full XBB.1.5 BA.2 spikes binding, entry, or escape from human sera. We find outside receptor-binding domain (RBD) have meaningfully impacted during evolution. also neutralization by serum individuals who recently had infections. The strongest are RBD at sites 357, 420, 440, 456, 473-however, antigenic impacts vary individuals. identify strong RBD; however many them decrease suggesting they act modulating conformation. Notably, growth rates clades be explained substantial part measured effects on phenotypes, our data could enable better prediction

Language: Английский

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Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4281 - 4281

Published: April 12, 2024

In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with host cell receptor ACE2 and panel diverse class one antibodies. The central objective investigation was to examine molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing antibody evasion variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, XBB.1.5 + L455F/F456L. By combining evolutionary analysis, dynamics simulations, ensemble-based mutational scanning protein residues in complexes ACE2, identified structural stability affinity are consistent results biochemical studies. agreement deep experiments, our quantitative analysis correctly reproduced strong variant-specific effects BA.2 variants. It shown Y453W F456L mutations can enhance when coupled Q493 while these become destabilized R493 position variant. provided rationale mechanism variants, showing role Q493/R493 hotspot modulating between sites L455F lineages. receptors antibodies provide experimental evidence interactions physically proximal Y501, R498, Q493, L455F, determine binding, F486P instrumental mediating broad resistance. supports which impact on is mediated through small group universal hotspots, effect immune could be more variant-dependent modulated by conformationally adaptable regions.

Language: Английский

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SARS-CoV-2 Omicron: Viral Evolution, Immune Evasion, and Alternative Durable Therapeutic Strategies

Viruses, Journal Year: 2024, Volume and Issue: 16(5), P. 697 - 697

Published: April 28, 2024

Since the SARS-CoV-2 Omicron virus has gained dominance worldwide, its continual evolution with unpredictable mutations and patterns revoked all authorized immunotherapeutics. Rapid viral also necessitated several rounds of vaccine updates in order to provide adequate immune protection. It remains imperative understand how evolves into different subvariants causes escape as this could help reevaluate current intervention strategies mostly implemented clinics emergency measures counter pandemic and, importantly, develop new solutions. Here, we a review focusing on major events evolution, including features spike mutation that lead evasion against monoclonal antibody (mAb) therapy vaccination, suggest alternative durable options such ACE2-based experimental therapies superior mAbs address unprecedented virus. In addition, type unique virus-trapping molecules can zoonotic SARS coronaviruses, either from unknown animal hosts or established wild-life reservoirs SARS-CoV-2, even seasonal alpha coronavirus NL63 depends human ACE2 for infection.

Language: Английский

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Deep mutational scanning and CRISPR-engineered viruses: tools for evolutionary and functional genomics studies

mSphere, Journal Year: 2025, Volume and Issue: unknown

Published: April 24, 2025

ABSTRACT Recent advancements in synthetic biology and sequencing technologies have revolutionized the ability to manipulate viral genomes with unparalleled precision. This review focuses on two powerful methodologies: deep mutational scanning CRISPR-based genome editing, that enable comprehensive mutagenesis detailed functional characterization of proteins. These approaches significantly deepened our understanding molecular determinants driving evolution adaptation. Furthermore, we discuss how these advances provide transformative insights for future vaccine development therapeutic strategies.

Language: Английский

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Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(10), P. e1012650 - e1012650

Published: Oct. 28, 2024

The recurring spillover of pathogenic coronaviruses and demonstrated capacity sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need better understand immune responses this virus family. For purpose, we characterized functional breadth potency antibodies targeting receptor binding domain (RBD) spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 sarbecoviruses from diverse clades animal origins with potential. One neutralizing antibody, C68.61, showed remarkable neutralization both variants viruses different sarbecovirus clades. which targets a conserved RBD class 5 epitope, did not select for escape or culture nor have predicted among circulating strains, suggesting epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive target more sequence 4 epitopes within show activity subset one antibody every single tested. A these Fc-mediated effector functions as potent impact infection outcome models. Thus, our study regions across may serve therapeutics pandemic preparedness well blueprints design immunogens capable eliciting cross-neutralizing responses.

Language: Английский

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A deep learning approach predicting the activity of COVID-19 therapeutics and vaccines against emerging variants

npj Systems Biology and Applications, Journal Year: 2024, Volume and Issue: 10(1)

Published: Nov. 27, 2024

Understanding which viral variants evade neutralization is crucial for improving antibody-based treatments, especially with rapidly evolving viruses like SARS-CoV-2. Yet, conventional assays are labor intensive and cannot capture the full spectrum of variants. We present a deep learning approach to predict changes in neutralizing antibody activity COVID-19 therapeutics vaccine-elicited sera/plasma against emerging Our leverages data 67,885 unique SARS-CoV-2 Spike sequences 7,069 vitro assays. The resulting model accurately predicted fold (R2 = 0.77) test set (N 980) collected up eight months after training data. Next, was used current therapeutic vaccine-induced antibodies lineages. Consistent other work, we found significantly reduced newer XBB descendants, notably EG.5, FL.1.5.1, XBB.1.16; primarily attributed F456L spike mutation.

Language: Английский

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A deep learning framework for predicting the neutralizing activity of COVID-19 therapeutics and vaccines against evolving SARS-CoV-2 variants

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 26, 2023

Abstract Understanding how viral variants evade neutralization is crucial for improving antibody-based treatments, especially with rapidly evolving viruses like SARS-CoV-2. Yet, conventional assays are limited in the face of rapid evolution, relying on a narrow set isolates, and falling short capturing full spectrum variants. To address this, we have developed deep learning approach to predict changes neutralizing antibody activity COVID-19 therapeutics vaccines against emerging First, trained variational autoencoder (VAE) using all 67,885 unique SARS-CoV-2 spike protein sequences from NCBI virus (up October 31, 2022) database encode into latent space. Using this VAE curated dataset 7,069 vitro assay data points NCATS OpenData Portal, neural network regression model fold 40 sequence variants, relative their ancestral strain (Wuhan-Hu-1). Our also employs Bayesian inference quantify prediction uncertainty, providing more nuanced informative estimates. validate model’s predictive capacity, assessed its performance test collected up eight months after included training (N = 980). The accurately predicted prospective dataset, an R 2 0.77. Expanding our methodology include available Portal date, current monoclonal antibodies newly identified lineages. predictions suggest that therapeutic vaccine-induced will significantly reduced newer XBB descendants, notably EG.5, FL.1.5.1, XBB.1.16. model, were able primarily attribute observed loss F456L mutation found EG.5 FL.1.5.1 sequences. Conversely, mRNA-bivalent be less susceptible recent BA.2.86 variant compared new descendants. These findings align closely research, underscoring potential shaping vaccine strategies

Language: Английский

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AlphaFold2-Enabled Atomistic Modeling of Epistatic Binding Mechanisms for the SARS-CoV-2 Spike Omicron XBB.1.5, EG.5 and FLip Variants: Convergent Evolution Hotspots Cooperate to Control Stability and Conformational Adaptability in Balancing ACE2 Binding and Antibody Resistance

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 12, 2023

Abstract In this study, we combined AI-based atomistic structural modeling and microsecond molecular simulations of the SARS-CoV-2 Spike complexes with host receptor ACE2 for XBB.1.5+L455F, XBB.1.5+F456L(EG.5) XBB.1.5+L455F/F456L (FLip) lineages to examine mechanisms underlying role convergent evolution hotspots in balancing binding antibody evasion. Using ensemble-based mutational scanning spike protein residues physics-based rigorous computations affinities, identified energy characterized basis epistatic couplings between hotspots. Consistent experiments, results revealed mediating Q493 hotspot synchronization L455F F456L mutations providing a quantitative insight into mechanism differences XBB lineages. Mutational profiling is network-based model showing that Q493, L455 F456 sites mediate stable communities at interface can serve as mediators non-additive couplings. Structure-based analysis class 1 antibodies quantified critical F486P eliciting strong immune evasion response. The support which emergence EG.5 FLip variants may have been dictated by leveraging effects several revolutionary provide synergy improved broad neutralization resistance. This interpretation consistent notion functionally balanced substitutions simultaneously optimize high affinity continue emerge through beneficial pair or triplet combinations RBD involving highly adaptable regions.

Language: Английский

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