Effect of natural and engineered variations on structure and biophysics of SARS-CoV-2 spike

自然和工程变异对 SARS-CoV-2 刺突结构和生物物理学的影响

• 批准号: 10453964
• 负责人: Priyamvada Acharya
• 金额: $ 76.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453964
• 关键词: 2019-nCoV; Antibodies; Antigens; Biochemical; Biochemistry; Biological; Biophysics; COVID-19; Communication; Computing Methodologies; Coronavirus; Coronavirus spike protein; Cryoelectron Microscopy; Data; Data Set; Electron Microscopy; Emergency Situation; Engineering; Evolution; Fc Receptor; Funding; Future; Goals; Grant; Immune Evasion; In Vitro; Kinetics; Lead; Life Cycle Stages; Link; Measures; Methods; Mink; Molecular; Molecular Conformation; Mutagenesis; Mutation; Negative Staining; Pathogenesis; Peptide Hydrolases; Peptides; Population; Positioning Attribute; Predisposition; Property; Protein Conformation; Proteins; Proteolysis; Protomer; Recurrence; Reporting; Research; Resistance; Resolution; Role; SARS-CoV-2 B.1.1.7; SARS-CoV-2 B.1.351; SARS-CoV-2 B.1.617.2; Site; Structure; Surface; TMPRSS2 gene; Techniques; Technology; United States National Institutes of Health; Vaccine Design; Vaccines; Variant; Viral; Virus; Work; X-Ray Crystallography; advanced simulation; base; betacoronavirus; biophysical analysis; combat; computer studies; design; expectation; experimental study; global health; health economics; in vivo; innovation; insight; neutralizing antibody; novel vaccines; pandemic disease; protein structure; receptor binding; reconstruction; structural biology; vaccine development; vaccine hesitancy; variants of concern

Effect of natural and engineered variations on structure and biophysics of SARS-CoV-2 spike COVID-19, caused by SARS-CoV-2, has devasted global health and economics. Vaccines are being deployed worldwide to gain control of the pandemic, although emergence of fast-spreading “variants of concern” (VOCs) have caused concern. Mutations in the spike (S) protein are under scrutiny due to its essential role in the virus life cycle, and being the dominant target of neutralizing antibodies. Widespread vaccine hesitancy and the current spread of the Delta variant provide fertile ground for emergence of vaccine- resistant variants. We and others have shown that variants use a plethora of strategies to modify antibody and receptor interactive surfaces, and spike conformation, resulting in antibody evasion and greater infectivity. Over the last two years, utilizing urgent supplement funding from the NIH, we studied the structures of SARS- CoV-2 S proteins and have established workflows spanning structure, biochemistry, biophysics and computation. Here we propose to continue the essential work of detangling the effects of variant S protein mutations, and to enhance our understanding of spike structure to further efforts to predict where the virus is heading and to inform novel vaccine designs. The scientific premise of this grant is that understanding spike structure and allostery will provide insights into its function, inform vaccine development, and provide mechanistic information essential for relating spike structure to beta-CoV replication, evolution, and immune evasion. The innovations in this grant derive from technologies we have developed for structural analyses of the S protein: an integrative structural biology pipeline combines cryo-electron microscopy (cryo-EM), Negative Stain Electron Microscopy (NSEM) and X-ray crystallography, with computational methods, and biochemical and biophysical analyses to study structural and functional properties of the spike, including furin cleavage, receptor binding, and antigenicity.

自然和工程变异对SARS-CoV-2刺突结构和生物物理的影响