Ensemble-Based Modeling of the SARS-CoV-2 Omicron BA.1 and BA.2 Spike Trimers and Systematic Characterization of Cryptic Binding Pockets in Distinct Functional States : Emergence of Conformation-Sensitive and Variant-Specific Allosteric Binding Sites DOI Open Access
Gennady M. Verkhivker, Mohammed Alshahrani,

Grace Gupta

et al.

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

Published: Aug. 23, 2023

Abstract A significant body of experimental structures the SARS-CoV-2 spike trimers for BA.1 and BA.2 variants revealed a considerable plasticity protein emergence druggable cryptic pockets. Understanding interplay conformational dynamics changes induced by Omicron identification dynamic binding pockets in S are paramount importance as exploring broad-spectrum antiviral agents to combat emerging is imperative. In current study we explore landscapes characterize universe multiple open closed functional states variants. By using combination atomistic simulations, network analysis, allostery-guided screening ensembles conformations, identified all experimentally known allosteric sites discovered variant-specific differences distribution trimers. This provided in-depth structural analysis predicted site context available information, revealing critical role effect on function sites. The results detailed how mutational pike can modulate across different regions protein. this particularly understanding bindings preferences Exploring present new previously underappreciated opportunity therapeutic intervention through conformation-selective targeting involved changes.

Language: Английский

Subsequent Waves of Convergent Evolution in SARS-CoV-2 Genes and Proteins DOI Creative Commons
Daniele Focosi, Pietro Giorgio Spezia, Fabrizio Maggi

et al.

Vaccines, Journal Year: 2024, Volume and Issue: 12(8), P. 887 - 887

Published: Aug. 5, 2024

Beginning in 2022, following widespread infection and vaccination among the global population, SARS-CoV-2 virus mainly evolved to evade immunity derived from vaccines past infections. This review covers convergent evolution of structural, nonstructural, accessory proteins SARS-CoV-2, with a specific look at common mutations found long-lasting infections that hint potentially reverting an enteric sarbecovirus type.

Language: Английский

Citations

5
Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features DOI Creative Commons
Craig A. Magaret, Li Li, Allan C. deCamp

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 11, 2024

Abstract In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe–critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 and 1,067 placebo recipients who acquired this set of prespecified analyses, we show that in Latin America, VE significantly lower Lambda vs. Reference non-Lambda [family-wise error rate (FWER) p < 0.05]. differed by residue match mismatch vaccine-insert at 16 amino acid positions (4 FWER 0.05; 12 q-value ≤ 0.20); decreased with physicochemical-weighted Hamming distance vaccine-strain sequence for Spike, receptor-binding domain, N-terminal S1 (FWER 0.001); 0.05) strain measured 9 antibody-epitope escape scores 4 NTD neutralization-impacting features; (p = 0.011) neutralization resistance level vaccinee sera. COVID-19 stable across most features but distant viruses.

Language: Английский

Citations

4
Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites DOI Creative Commons
Gennady M. Verkhivker, Mohammed Alshahrani,

Grace Gupta

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(10), P. 2009 - 2009

Published: Sept. 27, 2023

A significant body of experimental structures SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity protein emergence druggable binding pockets. Understanding interplay conformational dynamics changes induced by Omicron identification cryptic dynamic pockets in S is paramount importance as exploring broad-spectrum antiviral agents to combat emerging imperative. In current study, we explore landscapes characterize universe multiple open closed functional states variants. By using combination atomistic simulations, network analysis, an allostery-guided screening ensembles conformations, identified all experimentally known allosteric sites discovered variant-specific differences distribution trimers. This study provided structural characterization predicted captured sites, revealing critical role modulating cross-talk between sites. We found that mutational variant can induce remodeling stabilization pocket N-terminal domain, while this drastically altered may no longer be available ligand variant. Our results site receptor-binding domain remains stable ranks most favorable but could become fragmented less probable conformations. also uncovered several formed at inter-domain inter-protomer interface, including regions S2 subunit stem helix region, which are consistent with residues transitions antibody recognition. The particularly understanding features proteins, well effects Omicron-variant-specific modulation preferential exploration present new previously underappreciated opportunity therapeutic interventions through conformation-selective targeting involved changes.

Language: Английский

Citations

8
Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2 DOI Creative Commons

Zijing Ruan,

Jiaxi Tang,

Mingtang Zeng

et al.

Open Life Sciences, Journal Year: 2023, Volume and Issue: 18(1)

Published: Jan. 1, 2023

Abstract Since the outbreak of novel coronavirus nearly 3 years ago, world’s public health has been under constant threat. At same time, people’s travel and social interaction have also greatly affected. The study focused on potential host targets SARS-CoV-2, CD13, PIKfyve, which may be involved in viral infection viral/cell membrane fusion stage SARS-CoV-2 humans. In this study, electronic virtual high-throughput screening for CD13 PIKfyve was conducted using Food Drug Administration-approved compounds ZINC database. results showed that dihydroergotamine, Saquinavir, Olysio, Raltegravir, Ecteinascidin had inhibitory effects CD13. Dihydroergotamine, Sitagliptin, Grazoprevir, Saquinavir could inhibit PIKfyve. After 50 ns molecular dynamics simulation, seven stability at active site target protein. Hydrogen bonds van der Waals forces were formed with proteins. good binding free energy after to proteins, providing drug candidates treatment prevention variants.

Language: Английский

Citations

2
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 DOI Open Access

Hao‐Chan Hung,

Boon‐Fatt Tan,

Wei‐Shuo Lin

et al.

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

Citations

0
Ensemble-Based Modeling of the SARS-CoV-2 Omicron BA.1 and BA.2 Spike Trimers and Systematic Characterization of Cryptic Binding Pockets in Distinct Functional States : Emergence of Conformation-Sensitive and Variant-Specific Allosteric Binding Sites DOI Open Access
Gennady M. Verkhivker, Mohammed Alshahrani,

Grace Gupta

et al.

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

Published: Aug. 23, 2023

Abstract A significant body of experimental structures the SARS-CoV-2 spike trimers for BA.1 and BA.2 variants revealed a considerable plasticity protein emergence druggable cryptic pockets. Understanding interplay conformational dynamics changes induced by Omicron identification dynamic binding pockets in S are paramount importance as exploring broad-spectrum antiviral agents to combat emerging is imperative. In current study we explore landscapes characterize universe multiple open closed functional states variants. By using combination atomistic simulations, network analysis, allostery-guided screening ensembles conformations, identified all experimentally known allosteric sites discovered variant-specific differences distribution trimers. This provided in-depth structural analysis predicted site context available information, revealing critical role effect on function sites. The results detailed how mutational pike can modulate across different regions protein. this particularly understanding bindings preferences Exploring present new previously underappreciated opportunity therapeutic intervention through conformation-selective targeting involved changes.

Language: Английский

Citations

0