Epimaps of the SARS-CoV-2 Receptor-Binding Domain Mutational Landscape: Insights into Protein Stability, Epitope Prediction, and Antibody Binding DOI Creative Commons
Eleni Pitsillou, Assam El‐Osta, Andrew Hung

et al.

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 301 - 301

Published: Feb. 18, 2025

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses an ongoing threat to the efficacy vaccines and therapeutic antibodies. Mutations predominantly affect receptor-binding domain (RBD) spike protein, which mediates viral entry. RBD is also a major target monoclonal antibodies that were authorised for use during pandemic. In this study, in silico approach was used investigate mutational landscape SARS-CoV-2 variants, including currently circulating Omicron subvariants. A total 40 single-point mutations assessed their potential effect on protein stability dynamics. Destabilising effects predicted such as L455S F456L, while stabilising R346T. Conformational B-cell epitope predictions subsequently performed wild-type (WT) variant RBDs. from located within residues regions found correspond sites targeted by Furthermore, homology models generated utilised protein-antibody docking. binding characteristics 10 against WT 14 evaluated. Through evaluating affinities, interactions, energy contributions residues, contributing evasion identified. findings study provide insight into structural molecular mechanisms underlying neutralising antibody evasion. Future development could focus broadly antibodies, engineering with enhanced affinity, targeting beyond RBD.

Language: Английский

Immune evasion, infectivity, and fusogenicity of SARS-CoV-2 BA.2.86 and FLip variants DOI Creative Commons
Panke Qu, Kai Xu, Julia N. Faraone

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(3), P. 585 - 595.e6

Published: Jan. 8, 2024

Evolution of SARS-CoV-2 requires the reassessment current vaccine measures. Here, we characterized BA.2.86 and XBB-derived variant FLip by investigating their neutralization alongside D614G, BA.1, BA.2, BA.4/5, XBB.1.5, EG.5.1 sera from 3-dose-vaccinated bivalent-vaccinated healthcare workers, XBB.1.5-wave-infected first responders, monoclonal antibody (mAb) S309. We assessed biology spikes measuring viral infectivity membrane fusogenicity. is less immune evasive compared to other XBB variants, consistent with antigenic distances. Importantly, distinct mAb S309 was unable neutralize BA.2.86, likely due a D339H mutation based on modeling. had relatively high fusogenicity in CaLu-3 cells but low fusion 293T-ACE2 some suggesting potentially different conformational stability spike. Overall, our study underscores importance surveillance need for updated COVID-19 vaccines.

Language: Английский

Citations

105
Immune evasion and membrane fusion of SARS-CoV-2 XBB subvariants EG.5.1 and XBB.2.3 DOI Creative Commons
Julia N. Faraone, Panke Qu,

Negin Goodarzi

et al.

Emerging Microbes & Infections, Journal Year: 2023, Volume and Issue: 12(2)

Published: Oct. 11, 2023

Immune evasion by SARS-CoV-2 paired with immune imprinting from monovalent mRNA vaccines has resulted in attenuated neutralizing antibody responses against Omicron subvariants. In this study, we characterized two new XBB variants rising circulation - EG.5.1 and XBB.2.3, for their neutralization syncytia formation. We determined the titers sera of individuals that received a bivalent vaccine booster, BA.4/5-wave infection, or XBB.1.5-wave infection. Bivalent vaccination-induced antibodies neutralized ancestral D614G efficiently, but to much less extent, XBB.2.3 variants. fact, enhanced escape appeared be driven its key defining mutation XBB.1.5-F456L. Notably, infection BA.4/5 XBB.1.5 afforded little, if any, EG.5.1, previous especially unvaccinated individuals, average near limit detection. Additionally, investigated infectivity, fusion activity, processing variant spikes HEK293T-ACE2 CaLu-3 cells found no significant differences compared earlier Overall, our findings highlight continued subvariants and, more importantly, need reformulate include better protection.

Language: Английский

Citations

70
Immune Evasion, Infectivity, and Fusogenicity of SARS-CoV-2 Omicron BA.2.86 and FLip Variants DOI
Panke Qu, Kai Xu, Julia N. Faraone

et al.

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

Published: Sept. 12, 2023

Evolution of SARS-CoV-2 requires the reassessment current vaccine measures. Here, we characterized BA.2.86 and XBB-lineage variant FLip by investigating their neutralization alongside D614G, BA.1, BA.2, BA.4/5, XBB.1.5, EG.5.1 sera from 3-dose vaccinated bivalent healthcare workers, XBB.1.5-wave infected first responders, monoclonal antibody (mAb) S309. We assessed biology Spikes measuring viral infectivity membrane fusogenicity. is less immune evasive compared to other XBB variants, consistent with antigenic distances. Importantly, distinct mAb S309 was unable neutralize BA.2.86, likely due a D339H mutation based on modeling. had relatively high fusogenicity in CaLu-3 cells but low fusion 293T-ACE2 some suggesting potentially differences conformational stability Spike. Overall, our study underscores importance surveillance need for updated COVID-19 vaccines.

Language: Английский

Citations

46
Mutations in the SARS-CoV-2 spike receptor binding domain and their delicate balance between ACE2 affinity and antibody evasion DOI Creative Commons

Song Xue,

Yuru Han, Fan Wu

et al.

Protein & Cell, Journal Year: 2024, Volume and Issue: 15(6), P. 403 - 418

Published: March 4, 2024

Intensive selection pressure constrains the evolutionary trajectory of SARS-CoV-2 genomes and results in various novel variants with distinct mutation profiles. Point mutations, particularly those within receptor binding domain (RBD) spike (S) protein, lead to functional alteration both engagement monoclonal antibody (mAb) recognition. Here, we review data RBD point mutations possessed by major discuss their individual effects on ACE2 affinity immune evasion. Many single amino acid substitutions epitopes crucial for evasion capacity may conversely weaken affinity. However, this weakened effect could be largely compensated specific epistatic such as N501Y, thus maintaining overall protein all variants. The predominant direction evolution lies neither promoting nor evading mAb neutralization but a delicate balance between these two dimensions. Together, interprets how efficiently resist meanwhile is maintained, emphasizing significance comprehensive assessment mutations.

Language: Английский

Citations

25
Key mechanistic features of the trade-off between antibody escape and host cell binding in the SARS-CoV-2 Omicron variant spike proteins DOI Creative Commons
Weiwei Li, Zepeng Xu, Tianhui Niu

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(8), P. 1484 - 1498

Published: March 11, 2024

Abstract Since SARS-CoV-2 Omicron variant emerged, it is constantly evolving into multiple sub-variants, including BF.7, BQ.1, BQ.1.1, XBB, XBB.1.5 and the recently emerged BA.2.86 JN.1. Receptor binding immune evasion are recognized as two major drivers for evolution of receptor domain (RBD) spike (S) protein. However, underlying mechanism interplay between factors remains incompletely understood. Herein, we determined structures human ACE2 complexed with XBB RBDs. Based on ACE2/RBD these sub-variants a comparison known complex structures, found that R346T substitution in RBD enhanced upon an interaction residue R493, but not Q493, via involving long-range conformation changes. Furthermore, R493Q F486V exert balanced impact, through which capability was somewhat compromised to achieve optimal binding. We propose “two-steps-forward one-step-backward” model describe such compromise affinity during sub-variants.

Language: Английский

Citations

21
Spike structures, receptor binding, and immune escape of recently circulating SARS-CoV-2 Omicron BA.2.86, JN.1, EG.5, EG.5.1, and HV.1 sub-variants DOI
Linjie Li, Kaiyuan Shi,

Yuhang Gu

et al.

Structure, Journal Year: 2024, Volume and Issue: 32(8), P. 1055 - 1067.e6

Published: July 15, 2024

Language: Английский

Citations

18
Enabling the immune escaped etesevimab fully-armed against SARS-CoV-2 Omicron subvariants including KP.2 DOI Creative Commons
Chao Su,

Juanhua He,

Yufeng Xie

et al.

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

Published: Jan. 1, 2025

Language: Английский

Citations

2
Neutralization of EG.5, EG.5.1, BA.2.86, and JN.1 by antisera from dimeric receptor-binding domain subunit vaccines and 41 human monoclonal antibodies DOI

Qingwen He,

Yaling An,

Xuemei Zhou

et al.

Med, Journal Year: 2024, Volume and Issue: 5(5), P. 401 - 413.e4

Published: April 3, 2024

Language: Английский

Citations

13
The rising SARS‐CoV‐2 JN.1 variant: evolution, infectivity, immune escape, and response strategies DOI Creative Commons
Yishan Lu, Danyi Ao,

Xuemei He

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(8)

Published: July 29, 2024

The JN.1 variant of COVID-19 has emerged as the dominant strain worldwide since end 2023. As a subclade BA.2.86 variant, harbors unique combination mutations inherited from lineage, notably featuring novel L455S mutation within its receptor-binding motif. This been linked to increased transmissibility and enhanced immune evasion capabilities. During rise JN.1, evidence resistance various monoclonal antibodies reduced cross-neutralization effects XBB.1.5 vaccine have observed. Although public health threat posed by appears relatively low, concerns persist regarding evolutionary trajectory under pressure. review provides comprehensive overview evolving highlighting need for continuous monitoring investigation new variants that could lead widespread infection. It assesses efficacy current vaccines therapeutics against emerging variants, particularly focusing on immunocompromised populations. Additionally, this summarizes potential advancements clinical treatments COVID-19, offering insights optimize prevention treatment strategies. thoroughly evaluates variant's impact implications future therapeutic development, contributing ongoing efforts mitigate risk virus transmission disease severity.

Language: Английский

Citations

9
SARS-CoV-2 serotyping based on spike antigenicity and its implications for host immune evasion DOI

Wenjing Ruan,

Pengyue Gao, Xiao Qu

et al.

EBioMedicine, Journal Year: 2025, Volume and Issue: 114, P. 105634 - 105634

Published: March 12, 2025

Language: Английский

Citations

1