A decoy receptor for SARS-CoV-2 For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter human cells, the spike protein on the surface of the virus must bind to the host receptor protein, angiotensin-converting enzyme 2 (ACE2). A soluble version of the receptor is being explored as a therapeutic. Chan et al. used deep mutagenesis to identify ACE2 mutants that bind more tightly to the spike protein and combined mutations to further increase binding affinity (see the Perspective by DeKosky). A promising variant was engineered to be a stable dimer that has a binding affinity for the spike protein; it is comparable with neutralizing antibodies and neutralized both SARS-CoV-2 and SARS-CoV-1 in a cell-based assay. In addition, the similarity to the natural receptor may limit the possibility for viral escape. Science, this issue p. 1261; see also p. 1167 A variant of ACE2 based on deep mutagenesis far outcompetes the natural receptor in binding the SARS-CoV-2 spike protein. The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds angiotensin-converting enzyme 2 (ACE2) on host cells to initiate entry, and soluble ACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. By using deep mutagenesis, mutations in ACE2 that increase S binding are found across the interaction surface, in the asparagine 90–glycosylation motif and at buried sites. The mutational landscape provides a blueprint for understanding the specificity of the interaction between ACE2 and S and for engineering high-affinity decoy receptors. Combining mutations gives ACE2 variants with affinities that rival those of monoclonal antibodies. A stable dimeric variant shows potent SARS-CoV-2 and -1 neutralization in vitro. The engineered receptor is catalytically active, and its close similarity with the native receptor may limit the potential for viral escape.

中文翻译：

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改造人类 ACE2 以优化与 SARS 冠状病毒 2 刺突蛋白的结合

SARS-CoV-2的诱饵受体对于严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）进入人体细胞，病毒表面的刺突蛋白必须与宿主受体蛋白血管紧张素转换酶2结合(ACE2)。正在探索受体的可溶性版本作为治疗剂。陈等人。使用深度诱变来鉴定与刺突蛋白结合更紧密的 ACE2 突变体，并结合突变以进一步增加结合亲和力（参见 DeKosky 的观点）。一种有前途的变体被设计成稳定的二聚体，对刺突蛋白具有结合亲和力；它与中和抗体相当，并在基于细胞的检测中中和了 SARS-CoV-2 和 SARS-CoV-1。此外，与天然受体的相似性可能会限制病毒逃逸的可能性。科学，这个问题 p。1261; 另见第 1167 基于深度诱变的 ACE2 变体在结合 SARS-CoV-2 刺突蛋白方面远远胜过天然受体。严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的刺突 (S) 蛋白与宿主细胞上的血管紧张素转换酶 2 (ACE2) 结合以启动进入，可溶性 ACE2 是一种治疗候选物，通过充当诱饵。通过使用深度诱变，在相互作用表面、天冬酰胺 90-糖基化基序和掩埋位点中发现了 ACE2 中增加 S 结合的突变。突变景观为理解 ACE2 和 S 之间相互作用的特异性以及设计高亲和力诱饵受体提供了蓝图。结合突变使 ACE2 变体具有与单克隆抗体相媲美的亲和力。一种稳定的二聚体变体在体外显示出有效的 SARS-CoV-2 和 -1 中和作用。工程受体具有催化活性，它与天然受体的相似性可能会限制病毒逃逸的可能性。