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

Nature Reviews Microbiology, Год журнала: 2022, Номер 21(2), С. 112 - 124

Опубликована: Окт. 28, 2022

Язык: Английский

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Structural diversity of the SARS-CoV-2 Omicron spike

Molecular Cell, Год журнала: 2022, Номер 82(11), С. 2050 - 2068.e6

Опубликована: Март 25, 2022

Язык: Английский

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Mutations of SARS-CoV-2 spike protein: Implications on immune evasion and vaccine-induced immunity

Seminars in Immunology, Год журнала: 2021, Номер 55, С. 101533 - 101533

Опубликована: Июнь 1, 2021

Responsible for more than 4.9 million deaths so far, COVID-19, caused by SARS-CoV-2, is instigating devastating effects on the global health care system whose impacts could be longer years to come. Acquiring a comprehensive knowledge of host-virus interaction critical designing effective vaccines and/or drugs. Understanding evolution virus and impact genetic variability host immune evasion vaccine efficacy helpful design novel strategies minimize emerging variants concern (VOC). Most under development in current use target spike protein owning its unique function receptor binding, relatively conserved nature, potent immunogenicity inducing neutralizing antibodies, being good T cell responses. However, SARS-CoV-2 strains are exhibiting which affect antibody-based therapies addition enhancing viral mechanisms. Currently, degree mutations immunity vaccination, ability confer protection against attracts much attention. This review discusses implications vaccine-induced forward directions contribute future studies focusing immunotherapies consider evolution. Combining derived from different regions that boost both humoral cellular wings adaptive best options cope with VOC.

Язык: Английский

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Early fusion intermediate of ACE2-using coronavirus spike acting as an antiviral target

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: 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, Год журнала: 2022, Номер 5(1)

Опубликована: Ноя. 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.

Язык: Английский

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Structural Plasticity and Immune Evasion of SARS-CoV-2 Spike Variants

Viruses, Год журнала: 2022, Номер 14(6), С. 1255 - 1255

Опубликована: Июнь 9, 2022

The global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly affected every human life and overloaded the health care system worldwide. Limited therapeutic options combined with consecutive waves infection emergence novel SARS-CoV-2 variants, especially variants concern (VOCs), have prolonged challenged its control. Spike (S) protein on surface is primary target exposed to host essential for virus entry into cells. parental (Wuhan-Hu-1 or USA/WA1 strain) S virus-specific component currently implemented vaccines. However, most prone mutations, potentially shifting dynamics virus-host interactions affecting conformational/structural profiles. Scientists rapidly resolved atomic structures VOCs elucidated molecular details these which can inform design S-directed therapeutics broadly protective Here, we discuss recent findings S-associated transmissibility immune evasion experimental approaches used profile properties. We summarize structural studies that document flexibility/plasticity potential roles accumulated mutations functions. focus interpretation insights mechanism underlying antibody cell-receptor binding.

Язык: Английский

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SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Cell Reports, Год журнала: 2022, Номер 40(7), С. 111220 - 111220

Опубликована: Авг. 1, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants concern (VOCs). Here, we examine the contribution NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta Kappa variants) NTDs generating pseudotyped lentivirus. We find that Delta on a or wild-type (WT) background increases S1/S2 cleavage efficiency virus entry, specifically lung cells airway organoids, through use TMPRSS2. exhibits increased fusogenicity could be conferred WT transfer. However, chimeras Omicron BA.1 BA.2 with do not show more efficient TMPRSS2 fusogenicity. conclude allosterically modulates spike-mediated functions context-dependent manner, allosteric interactions may lost when combining regions from distantly related VOCs.

Язык: Английский

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Viral Membrane Fusion: A Dance Between Proteins and Lipids

Annual Review of Virology, Год журнала: 2023, Номер 10(1), С. 139 - 161

Опубликована: Сен. 29, 2023

There are at least 21 families of enveloped viruses that infect mammals, and many contain members high concern for global human health. All have a dedicated fusion protein or complex enacts the critical genome-releasing membrane event is essential before viral replication within host cell interior can begin. Because all enter cells by fusion, it behooves us to know how proteins function. Viral also major targets neutralizing antibodies, hence they serve as key vaccine immunogens. Here we review current concepts about focusing on triggered, structural intermediates between pre- postfusion forms, their interplay with lipid bilayers engage. We discuss cellular therapeutic interventions thwart virus-cell fusion.

Язык: Английский

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In Silico Discovery of Small Molecule Modulators Targeting the Achilles’ Heel of SARS-CoV-2 Spike Protein

ACS Central Science, Год журнала: 2023, Номер 9(2), С. 252 - 265

Опубликована: Фев. 8, 2023

The spike protein of SARS-CoV-2 has been a promising target for developing vaccines and therapeutics due to its crucial role in the viral entry process. Previously reported cryogenic electron microscopy (cryo-EM) structures have revealed that free fatty acids (FFA) bind with protein, stabilizing closed conformation reducing interaction host cell vitro. Inspired by these, we utilized structure-based virtual screening approach against conserved FFA-binding pocket identify small molecule modulators which helped us six hits micromolar binding affinities. Further evaluation their commercially available synthesized analogs enabled discover series compounds better affinities solubilities. Notably, our identified exhibited similar proteins prototypic currently circulating Omicron BA.4 variant. Furthermore, cryo-EM structure compound SPC-14 bound could shift conformational equilibrium toward conformation, is human ACE2 (hACE2) inaccessible. Our targeting serve as starting point future development broad-spectrum COVID-19 intervention treatments.

Язык: Английский

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Markov State Models and Perturbation-Based Approaches Reveal Distinct Dynamic Signatures and Hidden Allosteric Pockets in the Emerging SARS-Cov-2 Spike Omicron Variant Complexes with the Host Receptor: The Interplay of Dynamics and Convergent Evolution Modulates Allostery and Functional Mechanisms

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(16), С. 5272 - 5296

Опубликована: Авг. 7, 2023

The new generation of SARS-CoV-2 Omicron variants displayed a significant growth advantage and increased viral fitness by acquiring convergent mutations, suggesting that the immune pressure can promote evolution leading to sudden acceleration evolution. In current study, we combined structural modeling, microsecond molecular dynamics simulations, Markov state models characterize conformational landscapes identify specific dynamic signatures spike complexes with host receptor ACE2 for recently emerged highly transmissible XBB.1, XBB.1.5, BQ.1, BQ.1.1 variants. Microsecond simulations Markovian modeling provided detailed characterization functional states revealed thermodynamic stabilization XBB.1.5 subvariant, which be contrasted more BQ.1 subvariants. Despite considerable similarities, mutations induce unique distributions states. results suggested variant-specific changes mobility in interfacial loops receptor-binding domain protein fine-tuned through crosstalk between could provide an evolutionary path modulation escape. By combining atomistic analysis perturbation-based approaches, determined important complementary roles mutation sites as effectors receivers allosteric signaling involved plasticity regulation communications. This study also hidden pockets control distribution flexible adaptable regions.

Язык: Английский

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