The spike S of SARS-CoV-2 recognizes ACE2 on the host cell membrane to initiate entry. Soluble decoy receptors, in which the ACE2 ectodomain is engineered to block S with high affinity, potently neutralize infection and, due to close similarity with the natural receptor, hold out the promise of being broadly active against virus variants without opportunity for escape. Here, we directly test this hypothesis. We find an engineered decoy receptor, sACE2.v2.4, tightly binds S of SARS-associated viruses from humans and bats, despite the ACE2-binding surface being a region of high diversity. Saturation mutagenesis of the receptor-binding domain (RBD) followed by in vitro selection, with wild type ACE2 and the engineered decoy competing for binding sites, failed to find S mutants that discriminate in favor of the wild type receptor. Variant N501Y in the RBD, which has emerged in a rapidly spreading lineage (B.1.1.7) in England, enhances affinity for wild type ACE2 20-fold but remains tightly bound to engineered sACE2.v2.4. We conclude that resistance to engineered decoys will be rare and that decoys may be active against future outbreaks of SARS-associated betacoronaviruses.

中文翻译：

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SARS-CoV-2的工程诱饵受体广泛结合蛋白S序列变异体

SARS-CoV-2的尖峰S识别宿主细胞膜上的ACE2以启动进入。可溶性诱饵受体（其中ACE2胞外域被设计为以高亲和力阻断S），有效地中和感染，并且由于与天然受体的相似性，因此有望对病毒变体具有广泛的活性而没有逃脱的希望。在这里，我们直接检验这个假设。我们发现，工程设计的诱饵受体sACE2.v2.4与人和蝙蝠的SARS相关病毒S紧密结合，尽管ACE2结合表面是高度多样性的区域。受体结合结构域（RBD）的饱和诱变，然后进行体外选择，其中野生型ACE2和工程诱饵竞争结合位点，未能找到可区分野生型受体的S突变体。RBD中的变体N501Y已出现在英格兰的一个快速传播的血统（B.1.1.7）中，可提高对野生型ACE2的亲和力20倍，但仍与工程sACE2.v2.4紧密结合。我们得出的结论是，对工程诱饵的抗药性将很罕见，而且诱饵可能会有效抵抗SARS相关的β冠状病毒的未来爆发。