Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry.
Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry.
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DOI：
10.1126/science.abm8143
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发表时间：
2022-01-28
期刊：
影响因子：
56.9
通讯作者：
Veesler, David
中科院分区：
文献类型：
--
作者：
Park, Young-Jun;De Marco, Anna;Starr, Tyler N.;Liu, Zhuoming;Pinto, Dora;Walls, Alexandra C.;Zatta, Fabrizia;Zepeda, Samantha K.;Bowen, John;Sprouse, Kaitlin S.;Joshi, Anshu;Giurdanella, Martina;Guarino, Barbara;Noack, Julia;Abdelnabi, Rana;Foo, Shi-Yan Caroline;Lempp, Florian A.;Benigni, Fabio;Snell, Gyorgy;Neyts, Johan;Whelan, Sean Pj;Virgin, Herbert W.;Bloom, Jesse D.;Corti, Davide;Pizzuto, Matteo Samuele;Veesler, David
了解广泛中和的sarbecvirus抗体反应是制定针对严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）变体和未来人畜共患sarbecovirus的对策的关键。我们描述了一种被命名为S2K146的人单克隆抗体的分离和特性，该抗体广泛中和属于SARS-CoV-和SARS-CoV-2相关的sarbecvirus分支的病毒，这些病毒使用血管紧张素转换酶2 （ACE2）作为进入受体。结构和功能研究表明，大多数直接结合S2K146的病毒残基也参与ACE2的结合。这使得抗体能够有效地抑制受体附着。S2K146对仓鼠的SARS-CoV-2 β变体攻击具有保护作用，病毒传代实验显示，S2K146对逃逸突变体的出现具有很高的屏障，使其成为临床开发的良好候选者。保守的ace2结合残基存在一个易感位点，可能被用于开发引发广泛sarbecvirus免疫的疫苗。中和抗体是抵御严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的关键防御手段。许多中和抗体靶向与人类ACE2受体结合有关的病毒刺突蛋白区域，即受体结合基元（RBM）。该蛋白的这一区域在SARS-CoV-2变异体之间存在差异，导致现有单克隆抗体治疗失败，并导致先前感染或接种疫苗引起的抗体逃避。Park等人描述了一种单克隆抗体，可中和多种sarbecoviruses，包括2003年SARS-CoV和SARS-CoV-2。该抗体也结合在RBM中，但针对的是更保守的残基，因为它们参与ACE2结合。该抗体可以抵抗SARS-CoV-2 β变体，并且Omicron变体中的任何单个突变都不会影响抗体的结合。一种抗体通过结合与ACE2相互作用的病毒残基来中和利用ACE2进入细胞的sarbecovirus。
Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV– and SARS-CoV-2–related sarbecovirus clades, which use angiotensin-converting enzyme 2 (ACE2) as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta variant challenge in hamsters, and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity. Neutralizing antibodies are a key defense against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many neutralizing antibodies target the region of the viral spike protein that is involved in binding to the human ACE2 receptor, known as the receptor binding motif (RBM). This region of the protein is divergent between SARS-CoV-2 variants, leading to failure of existing monoclonal antibody treatments and evasion of antibodies elicited by previous infection or vaccination. Park et al. describe a monoclonal antibody that neutralizes a broad range of sarbecoviruses, including both the 2003 SARS-CoV and SARS-CoV-2. This antibody also binds in the RBM, but targets residues that are more conserved because they are involved in ACE2 binding. The antibody protects against the SARS-CoV-2 Beta variant, and none of the individual mutations in the Omicron variant affected antibody binding. —VV An antibody neutralizes across sarbecoviruses that use ACE2 to enter cells by binding viral residues that interact with ACE2.
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影响因子：
48
作者：
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