Elucidating the molecular docking and binding dynamics of aptamers with spike proteins across SARS-CoV-2 variants of concern

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 14, 2025

DNA aptamers with high binding affinity against SARS-CoV-2 spike proteins have been selected and analyzed. To better understand the affinities between (S-proteins) of relevant variants concerns (VOCs), in silico vitro characterization are excellent approaches to implement. Here, we identified generated aptamer sequences targeting S-protein VOCs through systematic evolution ligands by exponential enrichment (SELEX). In , prediction was conducted, followed a step-by-step workflow for secondary tertiary structures determination, modeling, molecular docking target S-protein. The strategy limited only providing predictions possible outcomes based on scores, ranking complemented analysis using direct enzyme-linked oligonucleotides assay (ELONA), which showed dissociation constants ( K d ) within 32 nM–193 nM range across three significant VOCs. These highly specific (Alpha Apt, Delta Omicron Apt) can be further studied as potential candidates both diagnostic therapeutic applications.

Language: Английский

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Few-Shot Viral Variant Detection via Bayesian Active Learning and Biophysics

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

The early detection of high-fitness viral variants is critical for pandemic response, yet limited experimental resources at the onset variant emergence hinder effective identification. To address this, we introduce an active learning framework that integrates protein language model ESM3, Gaussian process with uncertainty estimation, and a bio-physical to predict fitness novel in few-shot setting. By benchmarking on past SARS-CoV-2 data, demonstrate our methods accelerates identification by up fivefold compared random sampling while requiring characterization fewer than 1% possible variants. We also benchmarked deep mutational scans effectively identifies sites are frequently mutated during natural evolution predictive advantage two years baseline strategies, particularly those enabling antibody escape preserving ACE2 binding. Through systematic analysis different acquisition show incorporating selection enables broader exploration sequence landscape, leading discovery evolutionarily distant but potentially dangerous Our results suggest this could serve as warning system identifying concerning emerging viruses potential before they achieve widespread circulation.

Language: Английский

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Antibody evasiveness of SARS-CoV-2 subvariants KP.3.1.1 and XEC

Cell Reports, Journal Year: 2025, Volume and Issue: 44(4), P. 115543 - 115543

Published: April 1, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and spread, it remains critical understand the functional consequences of mutations in dominant viral variants. The recombinant JN.1 subvariant XEC recently replaced KP.3.1.1 become most prevalent worldwide. Here, we measure vitro neutralization by human sera, monoclonal antibodies, soluble ACE2 (hACE2) receptor relative parental subvariants KP.3 JN.1. are slightly more resistant (1.3- 1.6-fold) than serum antigenically similar. Both also demonstrate greater resistance select antibodies hACE2, all which target top spike. Our findings suggest that upward motion receptor-binding domain spike may be partially hindered N-terminal XEC, allowing these better evade up position have a growth advantage.

Language: Английский

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In depth sequencing of a serially sampled household cohort reveals the within-host dynamics of Omicron SARS-CoV-2 and rare selection of novel spike variants

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(4), P. e1013134 - e1013134

Published: April 28, 2025

SARS-CoV-2 has undergone repeated and rapid evolution to circumvent host immunity. However, outside of prolonged infections in immunocompromised hosts, within-host positive selection rarely been detected. Here we combine daily longitudinal sampling individuals with replicate sequencing increase the accuracy lower threshold for variant calling. We sequenced 577 specimens from 105 a household cohort during BA.1/BA.2 period. Individuals exhibited extremely low viral diversity, estimated evolutionary rate. Within-host dynamics were dominated by genetic drift purifying selection. Positive was rare but highly concentrated spike. A Wright Fisher Approximate Bayesian Computational model identified at 14 loci 7 spike, including S:448 S:339. This detectable immune-mediated is unusual acute respiratory may be caused relatively narrow antibody repertoire early Omicron phase pandemic.

Language: Английский

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Structural and Energetic Insights into SARS-CoV-2 Evolution: Analysis of hACE2–RBD Binding in Wild-Type, Delta, and Omicron Subvariants

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3776 - 3776

Published: April 17, 2025

The evolution of SARS-CoV-2, particularly the emergence Omicron variants, has raised questions regarding changes in its binding affinity to human angiotensin-converting enzyme 2 receptor (hACE2). Understanding impact mutations on interaction between receptor-binding domain (RBD) spike protein and hACE2 is critical for evaluating viral transmissibility, immune evasion, efficacy therapeutic strategies. Here, we used molecular dynamics (MD) simulations energy calculations investigate structural energetic differences hACE2- RBD complexes wild-type (WT), Delta, subvariants. Our results indicate that Delta first variants showed highest second-highest among studied. Furthermore, while exhibit increased stability altered electrostatic potential at hACE2–RBD interface when compared ancestral WT, their strength does not consistently increase with evolution. Moreover, newer subvariants like JN.1 a bimodal conformational strategy, alternating high-affinity state low-affinity state, which could potentially facilitate evasion. These findings suggest that, addition enhanced affinity, other factors, such as evasion adaptability, shape SARS-CoV-2

Language: Английский

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Cryo-electron microscopy in the study of virus entry and infection

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: July 24, 2024

Viruses have been responsible for many epidemics and pandemics that impacted human life globally. The COVID-19 pandemic highlighted both our vulnerability to viral outbreaks, as well the mobilization of scientific community come together combat unprecedented threat humanity. Cryo-electron microscopy (cryo-EM) played a central role in understanding SARS-CoV-2 during continues inform about this evolving pathogen. Cryo-EM with its two popular imaging modalities, single particle analysis (SPA) cryo-electron tomography (cryo-ET), has contributed immensely structure viruses interactions define their cycles pathogenicity. Here, we review how cryo-EM informed three distinct viruses, which - HIV-1 infect humans, third, bacteriophages, bacteria. For focus is on surface glycoproteins are mediating host receptor binding, cell membrane fusion, while structure, capsid maturation, attachment bacterial infection initiation mechanism.

Language: Английский

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Structural Immunology of SARS‐CoV‐2

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 27, 2024

The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, escape mechanisms. Antibodies receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in variants. contrast, conserved regions, such as S2 stem helix fusion peptide, broader reactivity generally lower potency. However, several broadly have demonstrated exceptional efficacy against emerging variants, including latest omicron subvariants, underscoring potential vulnerable sites RBS-A RBS-D/CR3022. We also highlight public classes different protein. targeted present opportunities for germline-targeting vaccine strategies. Overall, developing escape-resistant, potent effective vaccines remains crucial combating future This review emphasizes importance identifying key utilizing antibody affinity maturation inform therapeutic design.

Language: Английский

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Prying the lid open: Atomic-level insights on sialoglycan-TMPRSS2 coordination in HKU1 entry

Cell, Journal Year: 2024, Volume and Issue: 187(16), P. 4147 - 4149

Published: Aug. 1, 2024

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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