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《bioRxiv，6月2日，Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody》

  • 来源专题：COVID-19科研动态监测
  • 编译者： xuwenwhlib
  • 发布时间：2020-06-03

  • Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

    Xiangxi Wang, Zhe Lv, Yong-Qiang Deng, Qing Ye, Lei Cao, Chun-Yun Sun, Changfa Fan, Weijin Huang, Shihui Sun, Yao Sun, Ling Zhu, Qi Chen, Nan Wang, Jianhui Nie, Zhen Cui, Dandan Zhu, Neil Shaw, Xiao-Feng Li, Qianqian Li, Liangzhi Xie, Youchun Wang, Zihe Rao, Cheng-Feng Qin

    doi: https://doi.org/10.1101/2020.06.02.129098

    Abstract

    The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 replication and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in 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 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.

  • 原文来源：https://www.biorxiv.org/content/10.1101/2020.06.02.129098v1
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  • 《Science，7月23日，Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-07-28
    • Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody Zhe Lv1,8,*, Yong-Qiang Deng2,*, Qing Ye2,*, Lei Cao1,*, Chun-Yun Sun3,*, Changfa Fan4,*, Weijin Hua Science 23 Jul 2020: eabc5881 DOI: 10.1126/science.abc5881 Abstract The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 titers in the infected lungs and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in 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 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.
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  • 《bioRxiv，6月10日，Potent synthetic nanobodies against SARS-CoV-2 and molecular basis for neutralization》
    • 来源专题：COVID-19科研动态监测
    • 编译者：xuwenwhlib
    • 发布时间：2020-06-11
    • Potent synthetic nanobodies against SARS-CoV-2 and molecular basis for neutralization View ORCID ProfileDianfan Li, View ORCID ProfileTingting Li, View ORCID ProfileHongmin Cai, View ORCID ProfileHebang Yao, View ORCID ProfileBingjie Zhou, Yapei Zhao, View ORCID ProfileWenming Qin, View ORCID ProfileCedric A.J. Hutter, Yanling Lai, Juan Bao, Jiaming Lan, Gary Wong, View ORCID ProfileMarkus Seeger, View ORCID ProfileDimitri Lavillette doi: https://doi.org/10.1101/2020.06.09.143438 Abstract SARS-CoV-2, the Covid-19 causative virus, adheres to human cells through binding of its envelope Spike protein to the receptor ACE2. The Spike receptor-binding domain (S-RBD) mediates this key event and thus is a primary target for therapeutic neutralizing antibodies to mask the ACE2-interacting interface. Here, we generated 99 synthetic nanobodies (sybodies) using ribosome and phage display. The best sybody MR3 binds the RBD with KD of 1.0 nM and neutralizes SARS-CoV-2 pseudovirus with IC50 of 0.40 μg/mL. Crystal structures of two sybody-RBD complexes reveal a common neutralizing mechanism through which the RBD-ACE2 interaction is competitively inhibited by sybodies. The structures allowed the rational design of a mutant with higher affinity and improved neutralization efficiency by ≈24-folds, lowering the IC50 from 12.32 to 0.50 μg/mL. Further, the structures explain the selectivity of sybodies between SARS-CoV strains. Our work presents an alternative approach to generate neutralizers against newly emerged viruses.
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