There is an urgent need for the ability to rapidly develop effective countermeasures for emerging biological threats, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the ongoing coronavirus disease 2019 (COVID-19) pandemic. We have developed a generalized computational design strategy to rapidly engineer de novo proteins that precisely recapitulate the protein surface targeted by biological agents, like viruses, to gain entry into cells. The designed proteins act as decoys that block cellular entry and aim to be resilient to viral mutational escape. Using our novel platform, in less than ten weeks, we engineered, validated, and optimized de novo protein decoys of human angiotensin-converting enzyme 2 (hACE2), the membrane-associated protein that SARS-CoV-2 exploits to infect cells. Our optimized designs are hyperstable de novo proteins (~18-37 kDa), have high affinity for the SARS-CoV-2 receptor binding domain (RBD) and can potently inhibit the virus infection and replication in vitro. Future refinements to our strategy can enable the rapid development of other therapeutic de novo protein decoys, not limited to neutralizing viruses, but to combat any agent that explicitly interacts with cell surface proteins to cause disease.

中文翻译：

---

从头开始设计ACE2蛋白诱饵来中和SARS-CoV-2。

迫切需要能够迅速开发出有效的对策，以应对正在出现的生物学威胁，例如导致正在进行的冠状病毒病2019（COVID-19）大流行的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）。我们已经开发了一种通用的计算设计策略，可以快速设计从头开始的蛋白质，该蛋白质可以精确地概括由病毒等生物制剂靶向的蛋白质表面，从而进入细胞。设计的蛋白质可作为诱饵来阻止细胞进入，并旨在抵抗病毒突变逃逸。使用我们的新型平台，在不到十周的时间内，我们设计，验证并优化了人类血管紧张素转化酶2（hACE2）的从头蛋白质诱饵，该蛋白质是SARS-CoV-2用来感染细胞的膜相关蛋白。我们优化的设计是超稳定的从头蛋白（〜18-37 kDa），对SARS-CoV-2受体结合域（RBD）具有高亲和力，并且可以有效地抑制病毒在体外的感染和复制。我们策略的未来改进可以使其他治疗性从头蛋白质诱饵迅速发展，而不仅限于中和病毒，还可以与任何明显与细胞表面蛋白质相互作用而引起疾病的物质作斗争。