Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody
Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody
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DOI：
10.1126/science.abc5881
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发表时间：
2020-09-18
期刊：
影响因子：
56.9
通讯作者：
Wang, Xiangxi
中科院分区：
文献类型：
--
作者：
Lv, Zhe;Deng, Yong-Qiang;Wang, Xiangxi
由严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）大流行导致了前所未有的公共卫生危机。目前还没有批准的疫苗或治疗剂用于治疗COVID-19。在这里，我们报告了人源化单克隆抗体，H 014，有效地中和SARS-CoV-2和SARS-CoV假病毒以及真正的SARS-CoV-2在纳摩尔浓度通过接合刺突（S）受体结合结构域（RBD）。在人血管紧张素转换酶2小鼠模型中，H 014给药降低了感染肺部的SARS-CoV-2滴度，并预防了肺部病理学。冷冻电子显微镜表征的SARS-CoV-2 S三聚体与H 014 Fab片段的复合物揭示了一个以前未表征的构象表位，这是只有在RBD是在一个开放的构象。生物化学、细胞学、病毒学和结构研究表明，H 014可阻止SARS-CoV-2与其宿主细胞受体的结合。针对SARS-CoV和SARS-CoV-2的可用中和抗体的表位分析揭示了广泛的交叉保护性表位。我们的研究结果强调了基于抗体的治疗干预在COVID-19治疗中的关键作用。
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we report a humanized monoclonal antibody, H014, that efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nanomolar concentrations by engaging the spike (S) receptor binding domain (RBD). H014 administration reduced SARS-CoV-2 titers in infected lungs and prevented pulmonary pathology in a human angiotensin-converting enzyme 2 mouse model. Cryo-electron microscopy characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a previously uncharacterized conformational epitope, which was only accessible when the RBD was in an open conformation. Biochemical, cellular, virological, and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncovered broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.