SARS-CoV-2 variant evasion of monoclonal antibodies based on in vitro studies

Nature Reviews Microbiology, Journal Year: 2022, Volume and Issue: 21(2), P. 112 - 124

Published: Oct. 28, 2022

Language: Английский

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

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

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SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Nov. 3, 2022

Abstract The trimeric spike (S) glycoprotein, which protrudes from the SARS-CoV-2 viral envelope, binds to human ACE2, initiated by at least one protomer’s receptor binding domain (RBD) switching a "down” (closed) an "up” (open) state. Here, we used large-scale molecular dynamics simulations and two-dimensional replica exchange umbrella sampling calculations with more than thousand windows aggregate total of 160 μ s simulation investigate this transition without glycans. We find that glycosylated has higher barrier opening also energetically favors down state over up Analysis S-protein pathway reveals glycans N165 N122 interfere hydrogen bonds between RBD N-terminal in state, while N343 can stabilize both states. Finally, estimate how epitope exposure for several known antibodies changes along path. BD-368-2 antibody’s is continuously exposed, explaining its high efficacy.

Language: Английский

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Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(13), P. 11287 - 11368

Published: May 20, 2022

Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus-host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component combating disease 2019 (COVID-19) due to their low cost, efficiency, fact that they are free from safety ethical constraints. Additionally, mechanism governs global transmission SARS-CoV-2 cannot be revealed individual experiments was discovered by integrating genotyping massive viral sequences, biophysical modeling protein-protein deep mutational data, learning, advanced mathematics. There exists a tsunami literature on molecular modeling, simulations, predictions related developments drugs, vaccines, antibodies, diagnostics. To provide readers with quick update about this literature, we present comprehensive systematic methodology-centered review. Aspects such as biophysics, bioinformatics, cheminformatics, machine mathematics discussed. review will beneficial researchers who looking ways contribute those interested status field.

Language: Английский

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Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk with altered NTD dynamics

eLife, Journal Year: 2023, Volume and Issue: 12

Published: March 17, 2023

SARS-CoV-2 emergent variants are characterized by increased viral fitness and each shows multiple mutations predominantly localized to the spike (S) protein. Here, amide hydrogen/deuterium exchange mass spectrometry has been applied track changes in S dynamics from variants. Our results highlight large differences across at two loci with impacts on stability. A significant enhancement stabilization first occurred emergence of D614G followed smaller, progressive subsequent Stabilization preceded altered N-terminal domain, wherein Omicron BA.1 showed largest magnitude increases relative other preceding Changes resulting detail evolutionary trajectory emerging These carry major implications for offer new insights into variant-specific therapeutic development.

Language: Английский

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Receptor-binding domain of SARS-CoV-2 is a functional αv-integrin agonist

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(3), P. 102922 - 102922

Published: Jan. 18, 2023

Among the novel mutations distinguishing SARS-CoV-2 from similar coronaviruses is a K403R substitution in receptor-binding domain (RBD) of viral spike (S) protein within its S1 region. This amino acid occurs near angiotensin-converting enzyme 2-binding interface and gives rise to canonical RGD adhesion motif that often found native extracellular matrix proteins, including fibronectin. Here, ability recombinant S1-RBD bind cell surface integrins trigger downstream signaling pathways was assessed compared with RGD-containing, integrin-binding fragments We determined supported fibronectin-null mouse embryonic fibroblasts as well primary human small airway epithelial cells, while RBD-coated microparticles attached monolayers cation-dependent manner. Cell dependent inhibited by blocking antibodies against αv β3 but not α5 or β1 integrins. Similarly, we observed direct binding αvβ3 αvβ6 integrins, α5β1 using plasmon resonance. initiated spreading, focal formation, actin stress fiber organization extent Moreover, stimulated tyrosine phosphorylation mediators FAK, Src, paxillin; triggered Akt activation; proliferation. Thus, sequence can function an αv-selective integrin agonist. study provides evidence αv-containing respond functionally raises possibility S1-mediated dysregulation dynamics may contribute pathogenesis and/or post-acute sequelae infection.

Language: Английский

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Modelling how increased Cathepsin B/L and decreased TMPRSS2 usage for cell entry by the SARS-CoV-2 Omicron variant may affect the efficacy and synergy of TMPRSS2 and Cathepsin B/L inhibitors

Journal of Theoretical Biology, Journal Year: 2023, Volume and Issue: 572, P. 111568 - 111568

Published: July 1, 2023

The SARS-CoV-2 Omicron variant harbours many mutations in its spike protein compared to the original strain, which may alter ability enter cells, cell tropism, and response interventions blocking virus entry. To elucidate these effects, we developed a mathematical model of entry into target cells applied it analyse recent vitro data. can via two pathways, one using host proteases Cathepsin B/L other protease TMPRSS2. We found enhanced efficiency where strain preferentially used reduced thus appears have evolved use pathway better but at expense TMPRSS2 strain. estimated >4-fold >3-fold or strains type-dependent manner. Our predicted that inhibitors would be more efficacious less than Furthermore, predictions suggested drugs simultaneously targeting pathways exhibit synergy. maximum synergy drug concentrations yielding differ for findings provide insights mechanisms implications intervention mechanisms.

Language: Английский

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N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease

Biomolecules, Journal Year: 2024, Volume and Issue: 14(3), P. 282 - 282

Published: Feb. 27, 2024

Glycosylation, a prevalent post-translational modification, plays pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital infections, and inflammation. This review delves into the interplay between protein conformation, with specific focus on profound impact N-glycans selection distinct conformations characterized interactomes—namely, assemblies—under normal pathological conditions across various diseases. We begin examining spike SARS virus, illustrating how regulate infectivity pathogenic agents. Subsequently, we utilize prion chaperone glucose-regulated 94 as examples, exploring instances where N-glycosylation transforms physiological structures disease-associated forms. Unraveling these connections provides valuable insights potential therapeutic avenues deeper comprehension molecular intricacies that underlie disease conditions. exploration glycosylation’s influence conformation effectively bridges gap glycome disease, offering comprehensive perspective implications targeting conformational mutants their pathologic assemblies The goal unravel nuances modifications, shedding light they contribute assembly, disease.

Language: Английский

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The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour

Computational and Structural Biotechnology Journal, Journal Year: 2021, Volume and Issue: 20, P. 139 - 147

Published: Dec. 11, 2021

The SARS-CoV-2 spike protein is the first contact point between virus and host cells mediates membrane fusion. Recently, a fatty acid binding site was identified in (Toelzer

Language: Английский

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Spike Protein Mutation-Induced Changes in the Kinetic and Thermodynamic Behavior of Its Receptor Binding Domains Explain Their Higher Propensity to Attain Open States in SARS-CoV-2 Variants of Concern

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(10), P. 1894 - 1904

Published: Sept. 21, 2023

Spike (S) protein opening in SARS-CoV-2 controls the accessibility of its receptor binding domains (RBDs) to host receptors and immune recognition. Along evolution variants concern (VOC)─alpha, beta, gamma, delta, omicron─their S proteins showed a higher propensity attain open states. Deciphering how mutations can shape conformational dynamics will contribute understanding viral tropism. Here using microsecond-scale multiple molecular simulations (MDS), we provide insights into kinetic thermodynamic contributions these RBD pathways VOCs. Mutational effects were analyzed atomistic (i) equilibrium MDS closed states (ii) nonequilibrium for closed-to-open transitions. In or states, RBDs VOCs lower stability with fluctuations, compared ancestral SARS-CoV-2. For transitions VOCs, observed apparently faster 1.5–2-fold decrease free-energy barrier (ΔGclosed→open). Saturation mutagenesis studies highlighted that may control presentation receptors.

Language: Английский

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