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Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.

双副特应性和多价VH结构域阻断ACE2结合并中和SARS-CoV-2。

  • 影响因子:9.33
  • DOI:10.1038/s41589-020-00679-1
  • 作者列表:"Bracken CJ","Lim SA","Solomon P","Rettko NJ","Nguyen DP","Zha BS","Schaefer K","Byrnes JR","Zhou J","Lui I","Liu J","Pance K","QCRG Structural Biology Consortium.","Zhou XX","Leung KK","Wells JA
  • 发表时间:2021-01-01
Abstract

:Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 4.0 nM (180 ng ml-1). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy.

摘要

: 治疗和预防SARS-CoV-2迫切需要针对新型冠状病毒肺炎的中和剂。在这里,我们提出了一种针对中和表位快速鉴定和组装合成的人可变重 (VH) 结构域的策略。我们构建了VH-噬菌体文库,并靶向SARS-CoV-2 Spike受体结合域 (Spike-RBD) 的血管紧张素转化酶2 (ACE2) 结合界面。使用掩蔽选择方法,我们鉴定了两个非重叠表位的VH结合物,并将它们进一步组装为多价和双副特应性形式。与独立的VH结构域相比,这些VH构建体在假型SARS-CoV-2病毒上显示出增加的对刺突的亲和力 (高达600倍) 和中和效力 (高达1,400倍)。最有效的结合剂,一种三价VH,中和了真正的SARS-CoV-2,其半数最大抑制浓度 (IC50) 为4.0 nm (180 ng ml-1)。与Spike结合的三价VH的cryo-EM结构显示每个VH结构域在ACE2结合位点接合RBD,证实了我们的原始设计策略。

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