Structural and molecular basis of the epistasis effect in enhanced affinity between SARS-CoV-2 KP.3 and ACE2 DOI Creative Commons
Leilei Feng, Zhaoxi Sun, Yuchen Zhang

et al.

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

Published: Sept. 4, 2024

Abstract The recent emergence of SARS-CoV-2 variants KP.2 and KP.3 has been marked by mutations F456L/R346T F456L/Q493E, respectively, which significantly impact the virus’s interaction with human ACE2 its resistance to neutralizing antibodies. KP.3, featuring F456L Q493E, exhibits a markedly enhanced binding affinity compared JN.1 variant due synergistic effects between these mutations. This study elucidated structures RBD in complex using cryogenic electron microscopy (Cryo-EM) decipher structural thermodynamic implications on receptor molecular dynamics (MD) simulations, revealing that mutation facilitates more favorable environment for leading stronger interactions consequently enhance potential incorporating additional evasive These results underscore importance understanding mutational epistatic predicting evolution optimizing vaccine updates. Continued monitoring such is crucial anticipating new dominant strains preparing appropriate public health responses.

Language: Английский

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

Pei Li,

Julia N. Faraone, Cheng Chih Hsu

et al.

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

Published: Sept. 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.

Language: Английский

Citations

13
Neutralization and spike stability of JN.1-derived LB.1, KP.2.3, KP.3, and KP.3.1.1 subvariants DOI Creative Commons

Pei Li,

Julia N. Faraone, Cheng Chih Hsu

et al.

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

Published: March 26, 2025

ABSTRACT During the summer of 2024, coronavirus disease 2019 (COVID-19) cases surged globally, driven by variants derived from JN.1 subvariants severe acute respiratory syndrome 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 enhances NTD-receptor-binding (RBD) interaction, favoring RBD down conformation reducing accessibility specific nAbs. Moreover, introduces an N-linked glycan at N30, shielding recognition. These underscore role mutations immune evasion, stability, viral highlighting need consider DelS31-containing antigens updated COVID-19 vaccines. IMPORTANCE The emergence novel continues pose challenges for global public health, context evasion stability. study identifies key mutation, DelS31, JN.1-derived escape while stabilizes conformation, limits shedding, increases thermal resistance, possibly contribute prolonged persistence. Structural analyses reveal interactions introducing shielding, thus decreasing accessibility. emphasize critical shaping evolution underscoring urgent vaccines account adaptive changes.

Language: Английский

Citations

1
Pemivibart is less active against recent SARS-CoV-2 JN.1 sublineages DOI Open Access
Qian Wang, Yicheng Guo,

Jerren Ho

et al.

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

Published: Aug. 13, 2024

Abstract Protection from COVID-19 vaccination is suboptimal in many immunocompromised individuals. In March 2024, the Food and Drug Administration issued an Emergency Use Authorization for pemivibart (Permagard/VYD222), engineered human monoclonal antibody, pre-exposure prophylaxis this vulnerable population. However, SARS-CoV-2 has since evolved extensively, resulting multiple Omicron JN.1 sublineages. We therefore evaluated vitro neutralizing activity of against prevalent forms JN.1, including KP.2, KP.3, KP.2.3, LB.1, and, importantly, KP.3.1.1, which now expanding most rapidly. A panel VSV-based pseudoviruses representing major sublineages was generated to assess their susceptibility neutralization vitro. Structural analyses were then conducted understand impact specific spike mutations on virus-neutralization results. Pemivibart neutralized both KP.2 with comparable activity, whereas its potency decreased slightly KP.3 but substantially KP.3.1.1. Critically, 50% inhibitory concentration KP.3.1.1 ∼6 µg/mL, or ∼32.7 fold higher than that our study. suggest Q493E S31-deletion viral contribute antibody evasion, latter having a more pronounced effect. Our findings show lost substantial rapidly lineage today. Close monitoring clinical efficacy warranted. These results also highlight imperative expand arsenal preventive agents protect millions individuals who could not respond robustly vaccines.

Language: Английский

Citations

7
Structural and molecular basis of the epistasis effect in enhanced affinity between SARS-CoV-2 KP.3 and ACE2 DOI Creative Commons
Leilei Feng, Zhaoxi Sun, Yuchen Zhang

et al.

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

Published: Sept. 4, 2024

Abstract The recent emergence of SARS-CoV-2 variants KP.2 and KP.3 has been marked by mutations F456L/R346T F456L/Q493E, respectively, which significantly impact the virus’s interaction with human ACE2 its resistance to neutralizing antibodies. KP.3, featuring F456L Q493E, exhibits a markedly enhanced binding affinity compared JN.1 variant due synergistic effects between these mutations. This study elucidated structures RBD in complex using cryogenic electron microscopy (Cryo-EM) decipher structural thermodynamic implications on receptor molecular dynamics (MD) simulations, revealing that mutation facilitates more favorable environment for leading stronger interactions consequently enhance potential incorporating additional evasive These results underscore importance understanding mutational epistatic predicting evolution optimizing vaccine updates. Continued monitoring such is crucial anticipating new dominant strains preparing appropriate public health responses.

Language: Английский

Citations

4