Enabling the immune escaped etesevimab fully-armed against SARS-CoV-2 Omicron subvariants including KP.2

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

Published: Jan. 1, 2025

Language: Английский

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Structural insights into hybridoma-derived neutralizing monoclonal antibodies against Omicron BA.5 and XBB.1.16 variants of SARS-CoV-2

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

ABSTRACT The emergence of novel variants severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to pose an ongoing challenge for global public health services, highlighting the urgent need effective therapeutic interventions. Neutralizing monoclonal antibodies (mAbs) are a major strategy treatment COVID-19 and other viral diseases. In this study, we employed hybridoma technology generate mAbs that target BA.5 receptor-binding domain (RBD) SARS-CoV-2 spike protein. Through comprehensive screening process, identified four capable effectively neutralizing BA.5, XBB.1.16, related variant infections in vitro , among which ORB10 was found neutralize with plaque reduction neutralization test (PRNT 50 ) 8.7 ng/mL. Additionally, competitive binding assays, sequencing heavy light chain variable regions, kinetics characterization provided insights into epitopes affinities mAbs. Moreover, vivo experiments K18-hACE2 mouse model demonstrated protective efficacy against both XBB.1.16 variants. Finally, cryo-electron microscopy structural analysis ORB10–RBD complex key residues involved antibody–antigen interactions, providing molecular mechanisms immune escape Omicron from IMPORTANCE evolution has led evading responses elicited by natural infection vaccination, especially highly transmissible immune-evasive This study generated characterized panel specifically targeting RBD variant, showed . Cryo-EM further elucidated epitope interactions mechanism between enhances our understanding antibody-mediated provides valuable development strategies combat infections.

Language: Английский

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Rapid restoration of potent neutralization activity against the latest Omicron variant JN.1 via AI rational design and antibody engineering

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(6)

Published: Feb. 5, 2025

The rapid evolution of the viral genome has led to continual generation new variants SARS-CoV-2. Developing antibody drugs with broad-spectrum and high efficiency is a long-term task. It promising but challenging develop therapeutic neutralizing antibodies (nAbs) through in vitro based on antigen–antibody binding interactions. From an early B cell repertoire, we isolated 8G3 that retains its nonregressive activity against Omicron BA.1 various other strains vitro. protected ACE2 transgenic mice from WA1/2020 virus infection without adverse clinical manifestations completely cleared load lungs. Similar most IGHV3–53 antibodies, sites largely overlap, enabling competition for RBD. By comprehensively considering free energy changes complexes, biological environment their interactions, evolutionary direction were able select 50 mutants. Among them, 11 validated by experiments showing better activities. Further, combination four mutations identified increased neutralization potency JN.1, latest mutant, approximately 1,500-fold, one improvement multiple certain extent. Together, established procedure selection potent SARS-CoV-2 activity. Our results provide reference engineering future even pandemic viruses.

Language: Английский

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Conformational and Stability Analysis of SARS-CoV-2 Spike Protein Variants by Molecular Simulation

Pathogens, Journal Year: 2025, Volume and Issue: 14(3), P. 274 - 274

Published: March 12, 2025

We performed a comprehensive structural analysis of the conformational space several spike (S) protein variants using molecular dynamics (MD) simulations. Specifically, we examined four well-known (Delta, BA.1, XBB.1.5, and JN.1) alongside wild-type (WT) form SARS-CoV-2. The states each variant were characterized by analyzing their distributions within selected collective variables (CVs), such as inter-domain distances between receptor-binding domain (RBD) N-terminal (NTD). Our primary focus was to identify relevant potential transitions determine set native contacts (NCs) that stabilize these conformations. results reveal genetically more distant variants, JN.1, tend adopt compact compared WT. Additionally, exhibit novel NC profiles, an increased number specific distributed among ionic, polar, nonpolar residues. further analyzed impact mutations, including T478K, N500Y, Y504H. These mutations not only enhance interactions with human host receptor but also alter inter-chain stability introducing additional NCs Consequently, may influence accessibility certain regions neutralizing antibodies. Overall, findings contribute deeper understanding functional variations S variants.

Language: Английский

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Screened Fv-Antibodies against the Angiotensin-Converting Enzyme 2 (ACE2) Receptor Neutralizing the Infection of SARS-CoV-2

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(12), P. 3914 - 3920

Published: Nov. 19, 2024

For the prevention of SARS-CoV-2 infection, four Fv-antibodies with binding affinity for ACE2 receptor were screened from an Fv-antibody library. The expressed as soluble proteins and estimated to have a high affinity, comparable that between receptor. interaction was analyzed using docking simulation, significant attributed homology in amino acid sequence neutralizing activities demonstrated cell-based infection assay based on pseudo-virus types variant spike (Wild-type D614, Delta B.1.617.2, Omicron BA.2, BA.4/5).

Language: Английский

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Ultrapotent IgA dimeric antibodies neutralize emerging Omicron variants

Journal of Virology, Journal Year: 2024, Volume and Issue: 99(1)

Published: Dec. 4, 2024

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Defining a highly conserved B cell epitope in the receptor binding motif of SARS-CoV-2 spike glycoprotein

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Abstract SARS-CoV-2 mRNA vaccines induce robust and persistent germinal centre (GC) B cell responses in humans. It remains unclear how the continuous evolution of virus impacts breadth induced GC response. Using ultrasound-guided fine needle aspiration, we examined draining lymph nodes nine healthy adults following bivalent booster immunization. We show that 77.8% clones expressed as representative monoclonal antibodies recognized spike protein, with a third (37.8%) these targeting receptor binding domain (RBD). Strikingly, only one RBD-targeting mAb, mAb-52, neutralized all tested SARS- CoV-2 strains, including recent KP.2 variant. mAb-52 utilizes IGHV3-66 public clonotype, protects hamsters challenged against EG.5.1 variant targets class I/II RBD epitope, closely mimicking footprint ACE2. Finally, remarkable is due to somatic hypermutations accumulated within vaccine-induced reaction. One Sentence Summary Booster vaccine recruits broadens highly conserved site on glycoprotein.

Language: Английский

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Macromolecular interaction mechanism of the bacteriocin EntDD14 with the receptor binding domain (RBD) for the inhibition of SARS-CoV-2 and the JN.1 variant: Biomedical study based on elastic networks, stochastic Markov models, and macromolecular volumetric analysis

Biophysical Chemistry, Journal Year: 2024, Volume and Issue: 318, P. 107388 - 107388

Published: Dec. 29, 2024

Language: Английский

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