A decoy to neutralize SARS-CoV-2 Many efforts to develop therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are focused on the interaction between the spike protein, which decorates the surface of the virus, and its host receptor, human angiotensin-converting enzyme 2 (hACE2). Linsky et al. describe a de novo design strategy that allowed them to engineer decoy proteins that bind to the spike protein by replicating the hACE2 interface. The best decoy, CTC-445, bound with low nanomolar affinity, and selection of viral mutants that decrease binding is unlikely because this would also affect binding to hACE2. A bivalent version of CTC-445 bound even more tightly, neutralized SARS-CoV-2 infection of cells, and protected hamsters from a SARS-CoV-2 challenge. The stable decoy has the potential for respiratory therapeutic delivery. Science, this issue p. 1208 Designed de novo protein decoys neutralize SARS-CoV-2 in vitro and in vivo and are resilient to viral mutational escape. We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo human angiotensin-converting enzyme 2 (hACE2) decoys to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The best monovalent decoy, CTC-445.2, bound with low nanomolar affinity and high specificity to the receptor-binding domain (RBD) of the spike protein. Cryo–electron microscopy (cryo-EM) showed that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, showed ~10-fold improvement in binding. CTC-445.2d potently neutralized SARS-CoV-2 infection of cells in vitro, and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.

中文翻译：

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从头设计有效且有弹性的 hACE2 诱饵来中和 SARS-CoV-2

中和 SARS-CoV-2 的诱饵 许多开发针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的疗法的努力都集中在装饰病毒表面的刺突蛋白与其宿主受体之间的相互作用，人血管紧张素转换酶2 (hACE2)。林斯基等人。描述了一种从头设计策略，使他们能够通过复制 hACE2 界面来设计与刺突蛋白结合的诱饵蛋白。最好的诱饵 CTC-445 以低纳摩尔亲和力结合，并且不太可能选择减少结合的病毒突变体，因为这也会影响与 hACE2 的结合。CTC-445 的二价版本结合得更紧密，中和了细胞的 SARS-CoV-2 感染，并保护仓鼠免受 SARS-CoV-2 的攻击。稳定的诱饵具有呼吸治疗递送的潜力。科学，本期第 14 页。1208 从头设计的蛋白诱饵在体外和体内中和 SARS-CoV-2，并且能够抵抗病毒突变逃逸。我们开发了一种从头蛋白质设计策略，可以快速设计诱饵来中和利用细胞外宿主蛋白感染细胞的病原体。我们的管道允许从头设计、验证和优化人类血管紧张素转换酶 2 (hACE2) 诱饵，以中和严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)。最好的单价诱饵 CTC-445.2 以低纳摩尔亲和力和高特异性结合到刺突蛋白的受体结合域 (RBD)。冷冻电子显微镜 (cryo-EM) 显示该设计是准确的，并且可以同时结合单个刺突蛋白的所有三个 RBD。由于诱饵复制了 hACE2 中的刺突蛋白靶标界面，因此它本质上对病毒突变逃逸具有弹性。二价诱饵 CTC-445.2d 的结合能力提高了约 10 倍。CTC-445.2d 在体外有效中和了细胞的 SARS-CoV-2 感染，单次鼻内预防剂量的诱饵可以保护叙利亚仓鼠免受随后致命的 SARS-CoV-2 攻击。