Structure and Dynamics of the SARS-CoV-2 Spike Protein

SARS-CoV-2 刺突蛋白的结构和动力学

• 批准号: 10641865
• 负责人: WALTHER H MOTHES
• 金额: $ 82.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641865
• 关键词: 2019-nCoV; ACE2; Active Immunization; Address; Affect; Alveolar Macrophages; Antibodies; Antibody-mediated protection; Antigens; B-Lymphocytes; Binding; COVID-19; COVID-19 mortality; COVID-19 pandemic; Cathepsins; Cells; Clinical Trials; Coronavirus; Cryo-electron tomography; Cryoelectron Microscopy; Diagnostic Reagent Kits; Endosomes; Epitopes; Equilibrium; Fluorescence Resonance Energy Transfer; Glycoproteins; Herd Immunity; Imaging Techniques; Individual; Inflammatory Response; Laboratories; Ligands; Mediating; Methods; Molecular Conformation; Monitor; Mus; Passive Immunization; Pathogenicity; Patients; Peptide Hydrolases; Predisposition; Preparation; Process; Protein Dynamics; Proteins; Respiratory System; SARS coronavirus; SARS-CoV-2 immunity; SARS-CoV-2 spike protein; Sampling; Structure; Structure of parenchyma of lung; Surface; TMPRSS2 gene; Tissues; Tropism; Vaccines; Viral; Virion; Virus; Work; dimer; experimental study; in vivo; in vivo imaging; insight; mouse model; neutralizing antibody; nonhuman primate; particle; preference; receptor; receptor binding; response; single molecule; temporal measurement; vaccination strategy; vaccine development; vaccine trial

Summary The COVID19 pandemic may take 1-3 years and only fully subside once we reach herd immunity. Given the high mortality of COVID19, it is of critical importance to reach herd immunity through a vaccine. The viral spike glycoprotein (S) is central to our efforts for developing an effective vaccine immunogen. The S protein mediates viral entry into susceptible cells, is the primary target for antibodies, and is a widely used antigen in diagnostic kits. As such understanding the structure and dynamics of the S protein, and how antibodies engage it, is important to our response to COVID19. S consists of a trimer of S1/S2 dimers. S1 contains the receptor-binding domain (RBD) that interacts with receptor ACE2. S2 is further processed by proteases into S2' that mediates fusion. Structural insights into the S protein have been gained by single particle cryo electron microscopy (SP cryoEM) of a soluble trimer comprising most of the ectodomain, as well as by cryo electron tomography (cryoET) and SP cryoEM of native virus particles. These structural studies have revealed several distinct conformational prefusion states wherein the RBD domain points either up or down. Receptor ACE2 binds the RBD in the up conformation and stabilizes S in the `two-RBD-up' or `three-RBD-up' conformations. The observations of several distinct conformations at the EM level suggest that the S trimer exists in a conformational equilibrium. Real-time measurements of conformational dynamics of the S protein have not been performed. Many antibodies that bind and neutralize the S protein are being isolated from single B cells from recovered patients, or generated in mice, and their epitopes are being structurally characterized. Surprisingly, even though many antibodies clearly bind SARS-CoV-2 S, many do not neutralize the virus. Vaccine studies and clinical trials based on soluble RBD and S immunogens are under way. In general, they elicit antibodies and can protect from challenge in non-human primates and underscore our hope that a vaccine that develops antibodies against the S protein will be successful. However, the observation of non-neutralizing antibodies, a decline of antibodies in patients and worrisome evidence that antibody-bound coronavirus particles are responsible for the tissue-damaging inflammatory response seen in patients indicate that we need to know more about antibody mediated immunity against SARS-CoV-2. To address these challenges, the Mothes, Liu, Xiong and Blanchard laboratories will employ single molecule and in vivo imaging techniques to determine the structure and dynamics of ligand-free and antibody-bound SARS-CoV-2 S protein in the context of virus particles, and determine the fate of antibody-bound virus in vivo. Our work will inform active and passive immunization strategies against the COVID19 pandemic.

总结

项目成果

Immunogenicity and pre-clinical efficacy of an OMV-based SARS-CoV-2 vaccine.

基于 OMV 的 SARS-CoV-2 疫苗的免疫原性和临床前功效。

• DOI: 10.21203/rs.3.rs-2788726/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Grandi,Alberto;Tomasi,Michele;Ullah,Irfan;Bertelli,Cinzia;Vanzo,Teresa;Accordini,Silvia;Gagliardi,Assunta;Zanella,Ilaria;Benedet,Mattia;Corbellari,Riccardo;Lascio,GabrieleDi;Tamburini,Silvia;Caproni,Elena;Croia,Lorenzo;Ravà,M
• 通讯作者: Ravà,M

SARS-CoV-2 Variants Increase Kinetic Stability of Open Spike Conformations as an Evolutionary Strategy.

• DOI: 10.1128/mbio.03227-21
• 发表时间: 2021-02-22
• 期刊: mBio
• 影响因子: 6.4
• 作者: Yang Z;Han Y;Ding S;Shi W;Zhou T;Finzi A;Kwong PD;Mothes W;Lu M
• 通讯作者: Lu M

Vaccinia Virus Strain MVA Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models.

表达预灌注稳定的SARS-COV-2峰值糖蛋白的离发病毒菌株MVA可诱导强大的保护并防止小鼠和仓鼠模型中的脑感染。

• DOI: 10.3390/vaccines11051006
• 发表时间: 2023-05-21
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Lorenzo MM;Marín-López A;Chiem K;Jimenez-Cabello L;Ullah I;Utrilla-Trigo S;Calvo-Pinilla E;Lorenzo G;Moreno S;Ye C;Park JG;Matía A;Brun A;Sánchez-Puig JM;Nogales A;Mothes W;Uchil PD;Kumar P;Ortego J;Fikrig E;Martinez-Sobrido L;Blasco R
• 通讯作者: Blasco R

A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection.

• DOI: 10.1016/j.celrep.2022.110368
• 发表时间: 2022-02-15
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Beaudoin-Bussières G;Chen Y;Ullah I;Prévost J;Tolbert WD;Symmes K;Ding S;Benlarbi M;Gong SY;Tauzin A;Gasser R;Chatterjee D;Vézina D;Goyette G;Richard J;Zhou F;Stamatatos L;McGuire AT;Charest H;Roger M;Pozharski E;Kumar P;Mothes W;Uchil PD;Pazgier M;Finzi A
• 通讯作者: Finzi A

The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice.

• DOI: 10.1016/j.xcrm.2022.100893
• 发表时间: 2023-01-17
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Ullah, Irfan;Beaudoin-Bussieres, Guillaume;Symmes, Kelly;Cloutier, Marc;Ducas, Eric;Tauzin, Alexandra;Laumaea, Annemarie;Grunst, Michael W.;Dionne, Katrina;Richard, Jonathan;Begin, Philippe;Mothes, Walther;Kumar, Priti;Bazin, Renee;Finzi, Andres;Uchil, Pradeep D.
• 通讯作者: Uchil, Pradeep D.