登录
 机构网站
  1. 首页
  2. 情报产品
  3. 快讯详情

《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.

  • 原文来源：https://www.biorxiv.org/content/10.1101/2020.06.09.143438v1
122浏览量
原文链接
相关报告

  • 《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.
    176浏览量
    原文链接

  • 《Nature，10月20日，Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-11-16
    • Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2 Jianbo Dong, Betty Huang, Bo Wang, Allison Titong, Sachith Gallolu Kankanamalage, Zhejun Jia, Meredith Wright, Pannaga Parthasarathy & Yue Liu Scientific Reports volume 10, Article number: 17806 (2020) Abstract SARS-CoV-2 is a newly emergent coronavirus, which has adversely impacted human health and has led to the COVID-19 pandemic. There is an unmet need to develop therapies against SARS-CoV-2 due to its severity and lack of treatment options. A promising approach to combat COVID-19 is through the neutralization of SARS-CoV-2 by therapeutic antibodies. Previously, we described a strategy to rapidly identify and generate llama nanobodies (VHH) from naïve and synthetic humanized VHH phage libraries that specifically bind the S1 SARS-CoV-2 spike protein, and block the interaction with the human ACE2 receptor. In this study we used computer-aided design to construct multi-specific VHH antibodies fused to human IgG1 Fc domains based on the epitope predictions for leading VHHs. The resulting tri-specific VHH-Fc antibodies show more potent S1 binding, S1/ACE2 blocking, and SARS-CoV-2 pseudovirus neutralization than the bi-specific VHH-Fcs or combination of individual monoclonal VHH-Fcs. Furthermore, protein stability analysis of the VHH-Fcs shows favorable developability features, which enable them to be quickly and successfully developed into therapeutics against COVID-19.
    149浏览量
    原文链接