Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(12), P. e1011901 - e1011901

Published: Dec. 29, 2023

Substitutions that fix between SARS-CoV-2 variants can transform the mutational landscape of future evolution via epistasis. For example, large epistatic shifts in effects caused by N501Y underlied original emergence Omicron, but whether such saltations continue to define ongoing remains unclear. We conducted deep scans measure impacts all single amino acid mutations and single-codon deletions spike receptor-binding domain (RBD) on ACE2-binding affinity protein expression recent Omicron BQ.1.1 XBB.1.5 variants, we compared patterns earlier viral strains have previously profiled. As with previous scans, find many are tolerated or even enhance binding ACE2 receptor. The tolerance sites deletion largely conforms mutation. Though RBD not yet been seen dominant lineages, observe including at positions exhibit indel variation across broader sarbecovirus emerging interest, most notably well-tolerated Δ483 BA.2.86. substitutions distinguish induced as dramatic perturbations N501Y, identify drift interaction R493Q reversions 453, 455, 456, F456L defines XBB.1.5-derived EG.5 lineage. Our results highlight due epistasis, which may direct into new regions sequence space.

Language: Английский

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Deep mutational scanning of SARS-CoV-2 Omicron BA.2.86 and epistatic emergence of the KP.3 variant

Virus Evolution, Journal Year: 2024, Volume and Issue: 10(1)

Published: Jan. 1, 2024

Deep mutational scanning experiments aid in the surveillance and forecasting of viral evolution by providing prospective measurements effects on traits, but epistatic shifts impacts mutations can hinder when were made outdated strain backgrounds. Here, we report impact all single amino acid ACE2-binding affinity protein folding expression SARS-CoV-2 Omicron BA.2.86 spike receptor-binding domain. As with other variants, find a plastic evolvable basis for receptor binding, many at ACE2 interface maintaining or even improving affinity. Despite its large genetic divergence, have not diverged greatly from those measured BA.2 ancestor. However, do identify strong positive epistasis among subsequent that accrued descendants. Specifically, Q493E mutation decreased previous backgrounds is reversed sign to enhance human coupled L455S F456L currently emerging KP.3 variant. Our results point modest degree drift during recent highlight how these small important consequences emergence new variants.

Language: Английский

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Deep mutational scanning of SARS-CoV-2 Omicron BA.2.86 and epistatic emergence of the KP.3 variant

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

Published: July 24, 2024

Deep mutational scanning experiments aid in the surveillance and forecasting of viral evolution by providing prospective measurements effects on traits, but epistatic shifts impacts mutations can hinder when were made outdated strain backgrounds. Here, we report impact all single amino acid ACE2-binding affinity protein folding expression SARS-CoV-2 Omicron BA.2.86 spike receptor-binding domain (RBD). As with other variants, find a plastic evolvable basis for receptor binding, many at ACE2 interface maintaining or even improving affinity. Despite its large genetic divergence, have not diverged greatly from those measured BA.2 ancestor. However, do identify strong positive epistasis among subsequent that accrued descendants. Specifically, Q493E mutation decreased previous backgrounds is reversed sign to enhance human coupled L455S F456L currently emerging KP.3 variant. Our results point modest degree drift during recent highlight how these small important consequences emergence new variants.

Language: Английский

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Early 2022 breakthrough infection sera from India target the conserved cryptic class 5 epitope to counteract immune escape by SARS-CoV-2 variants

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

Published: March 26, 2025

ABSTRACT During the coronavirus disease 2019 (COVID-19) pandemic, vast majority of epitope mapping studies have focused on sera from mRNA-vaccinated populations high-income countries. In contrast, here, we report an analysis 164 serum samples isolated patients with breakthrough infection in India during early 2022 who received two doses ChAdOx viral vector vaccine. Sera were screened for neutralization breadth against wild-type (WT), Kappa, Delta, and Omicron BA.1 viruses. Three highest potency selected mapping, using charged scanning mutagenesis coupled yeast surface display next-generation sequencing. The mapped primarily targeted recently identified class 5 cryptic and, to a lesser extent, 1 4 epitopes. is completely conserved across all severe acute respiratory syndrome 2 (SARS-CoV-2) variants most sarbecoviruses. Based these observations, additional 26 characterized, showed broad neutralizing activity, including XBB.1.5. This contrast results obtained individuals receiving multiple original updated mRNA vaccines, where impaired XBB later concern (VOCs) observed. Our study demonstrates that vaccine highly exposed population sufficient drive substantial emerging upcoming concern. These data highlight important role hybrid immunity conferring protection inform future strategies protect rapidly mutating IMPORTANCE Worldwide implementation vaccines parallel emergence newer shaped humoral immune response population-specific manner. While characterizing this monitoring progression at level, it also imperative developing effective countermeasures form novel therapeutics. has implemented world’s second largest COVID-19 vaccination encountered large number post-vaccination “breakthrough” infections. From cohort infection, whose broadly different SARS-CoV-2 variants. Interestingly, target epitope, which was not previous population-level conducted Western rare remains variants, emerged ones SARS-like coronaviruses may cause outbreaks, thus representing potential vaccines.

Language: Английский

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Dual‐Locking the SARS‐CoV‐2 Spike Trimer: An Amphipathic Molecular “Bolt” Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 26, 2025

Abstract The SARS‐CoV‐2 spike (S) protein, a trimeric structure comprising three receptor binding domains (RBDs) and N‐terminal (NTDs), undergoes substantial conformational changes to fusion‐prone open state for angiotensin‐converting enzyme 2 (ACE2) host cell infection. Stabilizing its closed is key antiviral strategy but remains challenging. Here, we introduce S416, novel amphipathic molecule acting as “molecular bolt”. Cryo‐EM study reveals that S416 binds concurrently six sites across two distinct druggable interfaces: molecules at the RBD‐RBD interfaces NTD‐RBD interfaces. This unique “dual‐locking” mechanism, driven by S416's polar carboxyl head nonpolar phenylthiazole tail, robustly stabilizes trimer in locked, conformation through strong inter‐domain interactions, reducing structural flexibility atomic fluctuations compared apo resolved synchronously. Crucially, these are conserved human‐infecting coronaviruses, suggesting potential broad‐spectrum targets. Our findings demonstrate highly dynamic can be effectively stabilized an molecular bolt targeting both inter‐ intra‐monomer interfaces, offering promising against emerging coronaviruses.

Language: Английский

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Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

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

Published: Sept. 12, 2023

Substitutions that fix between SARS-CoV-2 variants can transform the mutational landscape of future evolution via epistasis. For example, large epistatic shifts in effects caused by N501Y underlied original emergence Omicron variants, but whether such saltations continue to define ongoing remains unclear. We conducted deep scans measure impacts all single amino acid mutations and single-codon deletions spike receptor-binding domain (RBD) on ACE2-binding affinity protein expression recent BQ.1.1 XBB.1.5 we compared patterns earlier viral strains have previously profiled. As with previous RBD scans, find many are tolerated or even enhance binding ACE2 receptor. The tolerance sites deletion largely conforms mutation. Though not yet been seen dominant lineages, observe including at positions exhibit indel variation across broader sarbecovirus emerging interest, most notably well-tolerated Δ483 BA.2.86. substitutions distinguish induced as dramatic perturbations N501Y, identify drift interaction R493Q reversions 453, 455, 456, like F456L newly EG.5 lineage. Our results highlight due epistasis, which may direct into new regions sequence space.

Language: Английский

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Epitope mapping via in vitro deep mutational scanning methods and its applications

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 108072 - 108072

Published: Dec. 1, 2024

Language: Английский

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Influence of Mutations on Physicochemical Properties of Spike Proteins from Prototypical SARS-CoV-2 Variants of Concern Detected in Amazonian Countries

Microbiology Research, Journal Year: 2024, Volume and Issue: 15(3), P. 1334 - 1345

Published: July 27, 2024

Since the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), viral spike protein (S) has become a target to describe appropriate epitopes for vaccine development and carry out epidemiological surveillance, especially regarding variants concern (VOCs). This study aimed evaluate influence mutations on physicochemical properties S proteins from prototypical SARS-CoV-2 VOCs detected in Amazonian countries. Using multiple computational tools, seven (B.1.1.7/P.1/B.1.617.2/BA.1/BA.2/BA.4/BA.5) were identified compared ancestral lineage virus (B). In all variants, most amino acids nonpolar; among polar acids, B.1.617.2/BA.1/BA.2/BA.4/BA.5 presented slightly higher proportion basic residues lower neutral residues. Unlike B.1.1.7/P.1/B.1.617.2, BA.1/BA.2 had greater content secondary structures, such as α-helices β-sheets. Regarding post-translational modifications, BA.2/BA.4/BA.5 fewer glycosylations phosphorylations. Finally, more prominent antigenic propensity N-terminal domain receptor-binding B.1.617.2/BA.4/BA.5 was observed. conclusion, omicron sequence variability other VOCs, influencing structural aspects that can potentially modulate its interaction with cellular receptors recognition by immune system.

Language: Английский

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Early 2022 breakthrough infection sera from India target the conserved cryptic class 5 epitope to counteract immune escape by SARS-CoV-2 variants

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

Published: July 8, 2024

Summary During the COVID-19 pandemic, vast majority of epitope mapping studies have focused on sera from mRNA-vaccinated populations high-income countries. In contrast, here we report an analysis 164 serum samples isolated breakthrough infection patients in India during early 2022 who received two doses ChAdOx viral vector vaccine. Sera were screened for neutralization breadth and potency against wildtype, Delta, Omicron BA.1 viruses amongst which three shortlisted using charged scanning mutagenesis. These majorly targeted recently identified class 5 cryptic is completely conserved across all SARS-CoV-2 variants different Sarbecoviruses. Consistent with these results, show broad neutralizing activity recent subvariants including XBB.1.5. Our study demonstrates that vaccinations vaccine a highly exposed population are sufficient to drive substantial emerging future concern.

Language: Английский

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Glycan masking of NTD loops with a chimeric RBD of the spike protein as a vaccine design strategy against emerging SARS‐CoV‐2 Omicron variants

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(9)

Published: Aug. 28, 2024

Abstract The N‐terminal domain (NTD) of the SARS‐CoV‐2 S protein comprises five exposed protruding loops. Deletions, insertions, and substitutions within these NTD loops play a significant role in viral evolution contribute to immune evasion. We reported previously that introducing glycan masking mutation R158N/Y160T loop led increased titers neutralizing antibodies against Wuhan‐Hu‐01 strain, as well Alpha, Beta, Delta variants. In this study, we conducted further investigations on 10 additional glycan‐masking sites Our findings indicate introduction mutations, specifically N87/G89T, H146N/N148T, N185/K187T, V213N/D215T significantly enhanced antibody variant. combination dual mutations R158N/Y160T+V213N/D215T R158N/Y160T+G219N results shift toward Omicron BA.1. Furthermore, receptor binding (RBD) alongside two Wuhan‐Hu‐1 XBB.1 sequences resulted noticeable antigenic distances, aligning with BA.4/5, BA.2.75.2, BQ.1.1, subvariants map. This strategic combination, which involves loops, along swap incorporating RBD, emerges promising vaccine design strategy for continuous development next‐generation vaccines.

Language: Английский

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