Recombinant XBB.1.5 boosters induce robust neutralization against KP.2- and KP.3-included JN.1 sublineages

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Янв. 27, 2025

Abstract The newly emerged variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) demonstrate resistance to present therapeutic antibodies as well the capability evade vaccination-elicited antibodies. JN.1 sublineages were demonstrated one most immune-evasive variants, showing higher neutralization compared XBB.1.5. In this study, serum samples collected from adult participants including those who had gone through BA.5/BF.7, EG.5/HK.3 and XBB/JN.1 infection waves, characterized by different vaccination histories. We evaluated in these against pseudoviruses Omicron lineages. further investigated humoral immune response recombinant XBB vaccines estimated sublineages, KP.2 KP.3. Our results showed that sera previous circulating subvariant breakthrough infections exhibited low GMTs 50% all tested significantly elevated individuals received WSK-V102C or WSK-V102D boosters. Importantly, 4 months after a booster XBB.1.5, JN.1, JN.1.13, KP.3 3479, 1684, 1397, 1247 1298, with 9.86-, 9.79-, 8.73-, 8.66- 8.16-fold increase without booster, respectively, indicating boosting XBB.1.5 subunit still induced strong antibody responses sublineages. However, KP.3, revealed more than 2-fold decreases neutralizing titers suggesting enhanced evasion necessity boosters based on

Язык: Английский

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Neutralization and Stability of JN.1-derived LB.1, KP.2.3, KP.3 and KP.3.1.1 Subvariants

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 5, 2024

SUMMARY During the summer of 2024, COVID-19 cases surged globally, driven by variants derived from JN.1 subvariants SARS-CoV-2 that feature new mutations, particularly in N-terminal domain (NTD) spike protein. In this study, we report on neutralizing antibody (nAb) escape, infectivity, fusion, and stability these subvariants—LB.1, KP.2.3, KP.3, KP.3.1.1. Our findings demonstrate all are highly evasive nAbs elicited bivalent mRNA vaccine, XBB.1.5 monovalent mumps virus-based or infections during BA.2.86/JN.1 wave. This reduction nAb titers is primarily a single serine deletion (DelS31) NTD spike, leading to distinct antigenic profile compared parental other variants. We also found DelS31 mutation decreases pseudovirus infectivity CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, protein appears more conformationally stable, as indicated reduced S1 shedding both without stimulation soluble ACE2, increased resistance elevated temperatures. Molecular modeling suggests induces conformational change stabilizes strengthens NTD-Receptor-Binding Domain (RBD) interaction, thus favoring down conformation RBD reducing accessibility ACE2 receptor certain nAbs. introduces an N-linked glycan modification at N30, shields underlying region recognition. data highlight critical role mutations for evasion, stability, viral suggest consideration updating vaccines antigens containing DelS31.

Язык: 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, Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

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Quantitative Characterization and Prediction of the Binding Determinants and Immune Escape Hotspots for Groups of Broadly Neutralizing Antibodies Against Omicron Variants: Atomistic Modeling of the SARS-CoV-2 Spike Complexes with Antibodies

Biomolecules, Год журнала: 2025, Номер 15(2), С. 249 - 249

Опубликована: Фев. 8, 2025

A growing body of experimental and computational studies suggests that the cross-neutralization antibody activity against Omicron variants may be driven by balance tradeoff between multiple energetic factors interaction contributions evolving escape hotspots involved in antigenic drift convergent evolution. However, dynamic details quantifying contribution these factors, particularly balancing nature specific interactions formed antibodies with epitope residues, remain largely uncharacterized. In this study, we performed molecular dynamics simulations, an ensemble-based deep mutational scanning SARS-CoV-2 spike binding free energy computations for two distinct groups broadly neutralizing antibodies: E1 group (BD55-3152, BD55-3546, BD5-5840) F3 (BD55-3372, BD55-4637, BD55-5514). Using approaches, examined determinants which potent can evade immune resistance. Our analysis revealed emergence a small number positions correspond to R346 K444 strong van der Waals act synchronously, leading large contribution. According our results, Abs effectively exploit hotspot clusters hydrophobic sites are critical functions along selective complementary targeting positively charged important ACE2 binding. Together conserved epitopes, lead expand breadth resilience neutralization shifts associated viral The results study demonstrate excellent qualitative agreement predicted mutations respect latest experiments on average scores. We argue epitopes leverage stability binding, while tend emerge synergistically electrostatic interactions.

Язык: Английский

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Mutational Scanning and Binding Free Energy Computations of the SARS-CoV-2 Spike Complexes with Distinct Groups of Neutralizing Antibodies: Energetic Drivers of Convergent Evolution of Binding Affinity and Immune Escape Hotspots

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(4), С. 1507 - 1507

Опубликована: Фев. 11, 2025

The rapid evolution of SARS-CoV-2 has led to the emergence variants with increased immune evasion capabilities, posing significant challenges antibody-based therapeutics and vaccines. In this study, we conducted a comprehensive structural energetic analysis spike receptor-binding domain (RBD) complexes neutralizing antibodies from four distinct groups (A–D), including group A LY-CoV016, B AZD8895 REGN10933, C LY-CoV555, D AZD1061, REGN10987, LY-CoV1404. Using coarse-grained simplified simulation models, energy-based mutational scanning, rigorous MM-GBSA binding free energy calculations, elucidated molecular mechanisms antibody escape mechanisms, identified key hotspots, explored evolutionary strategies employed by virus evade neutralization. residue-based decomposition revealed thermodynamic factors underlying effect mutations on binding. results demonstrate excellent qualitative agreement between predicted hotspots latest experiments escape. These findings provide valuable insights into determinants viral escape, highlighting importance targeting conserved epitopes leveraging combination therapies mitigate risk evasion.

Язык: Английский

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Biophysics of SARS-CoV-2 spike protein’s receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights

Biophysical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Март 8, 2025

Язык: Английский

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

Pathogens, Год журнала: 2025, Номер 14(3), С. 274 - 274

Опубликована: Март 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.

Язык: Английский

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Exploring Diverse Binding Mechanisms of Broadly Neutralizing Antibodies S309, S304, CYFN-1006 and VIR-7229 Targeting SARS-CoV-2 Spike Omicron Variants: Integrative Computational Modeling Reveals Balance of Evolutionary and Dynamic Adaptability in Shaping Molecular Determinants of Immune Escape

Опубликована: Апрель 17, 2025

Abstract Evolution of SARS-CoV-2 has led to the emergence variants with increased immune evasion capabilities, posing significant challenges antibody-based therapeutics and vaccines. The cross-neutralization activity antibodies against Omicron is governed by a complex delicate interplay multiple energetic factors interaction contributions. In this study, we conducted comprehensive analysis interactions between receptor-binding domain (RBD) spike protein four neutralizing S309, S304, CYFN1006, VIR-7229. Using integrative computational modeling that combined all-atom molecular dynamics (MD) simulations, mutational scanning, MM-GBSA binding free energy calculations, elucidated structural, energetic, dynamic determinants antibody binding. Our findings reveal distinct mechanisms evolutionary adaptation driving broad neutralization effect these antibodies. We show S309 targets conserved residues near ACE2 interface, leveraging synergistic van der Waals electrostatic interactions, while S304 focuses on fewer but sensitive residues, making it more susceptible escape mutations. CYFN-1006.1 CYFN-1006.2 highlights epitope coverage critical anchors at T345, K440, T346, enhancing its efficacy carrying K356T mutation which caused from broadly potent VIR-7229 XBB.1.5 EG.5 emphasized large structurally epitope, demonstrating certain adaptability compensatory effects F456L L455S Mutational profiling identified key crucial for binding, including P337, R346 T385 K386 underscoring their roles as "weak spots" balance viral fitness evasion. results demonstrate good agreement predicted hotspots mutations respect latest experiments average scores. study dissect importance targeting diverse epitopes counteract resistance. Broad-spectrum CYFN1006 maintain across achieve convergent evolution enabling tolerance in positions through structural interface. underscore diversity employed different basis high affinity excellent generation

Язык: Английский

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In Silico Design of miniACE2 Decoys with In Vitro Enhanced Neutralization Activity against SARS-CoV-2, Encompassing Omicron Subvariants

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(19), С. 10802 - 10802

Опубликована: Окт. 8, 2024

The COVID-19 pandemic has overwhelmed healthcare systems and triggered global economic downturns. While vaccines have reduced the lethality rate of SARS-CoV-2 to 0.9% as October 2024, continuous evolution variants remains a significant public health challenge. Next-generation medical therapies offer hope in addressing this threat, especially for immunocompromised individuals who experience prolonged infections severe illnesses, contributing viral evolution. These cases increase risk new emerging. This study explores miniACE2 decoys novel strategy counteract variants. Using silico design molecular dynamics, blocking proteins (BPs) were developed with stronger binding affinity receptor-binding domain multiple than naturally soluble human ACE2. BPs expressed E. coli tested vitro, showing promising neutralizing effects. Notably, BP9 exhibited an average IC50 4.9 µg/mL across several variants, including Wuhan strain, Mu, Omicron BA.1, BA.2 low demonstrates potent ability BP9, indicating its efficacy at concentrations.Based on these findings, emerged therapeutic candidate combating evolving thereby positioning it potential emergency biopharmaceutical.

Язык: Английский

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SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12079 - 12079

Опубликована: Ноя. 10, 2024

Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that abundantly present in the brain. It plays crucial role maintaining cellular structures and organelle functions, particularly supporting synaptic plasticity regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological begin to aggregate. This altered disrupts dopaminergic transmission causes both presynaptic postsynaptic dysfunction, ultimately leading cell death. A group of neurodegenerative diseases known as α-synucleinopathies characterized by intracellular accumulation deposits specific neuronal glial cells within certain brain regions. In addition Parkinson's disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), REM sleep behavior disorder (RBD). Given disorders are associated α-syn-related neuroinflammation-and considering SARS-CoV-2 infection has been shown affect nervous system, COVID-19 patients experiencing neurological symptoms-it proposed may contribute neurodegeneration PD other promoting misfolding aggregation. this review, we focus on whether could act an environmental trigger facilitates onset or progression α-synucleinopathies. Specifically, new evidence potential modulating function discuss causal relationship between development parkinsonism-like symptoms.

Язык: Английский

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