Xiao Tianshu, Lu Jianming, Zhang Jun, Johnson Rebecca I, McKay Lindsay G A, Storm Nadia, Lavine Christy L, Peng Hanqin, Cai Yongfei, Rits-Volloch Sophia, Lu Shen, Quinlan Brian D, Farzan Michael, Seaman Michael S, Griffiths Anthony, Chen Bing
bioRxiv. 2020 Sep 18:2020.09.18.301952. doi: 10.1101/2020.09.18.301952.
Effective intervention strategies are urgently needed to control the COVID-19 pandemic. Human angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that forms a dimer and serves as the cellular receptor for SARS-CoV-2. It is also a key negative regulator of the renin-angiotensin system (RAS), conserved in mammals, which modulates vascular functions. We report here the properties of a trimeric ACE2 variant, created by a structure-based approach, with binding affinity of ~60 pM for the spike (S) protein of SARS-CoV-2, while preserving the wildtype peptidase activity as well as the ability to block activation of angiotensin II receptor type 1 in the RAS. Moreover, the engineered ACE2 potently inhibits infection of SARS-CoV-2 in cell culture. These results suggest that engineered, trimeric ACE2 may be a promising anti-SARS-CoV-2 agent for treating COVID-19.
迫切需要有效的干预策略来控制新冠疫情。人血管紧张素转换酶2（ACE2）是一种羧肽酶，以二聚体形式存在，是新冠病毒的细胞受体。它也是肾素-血管紧张素系统（RAS）的关键负调节因子，在哺乳动物中保守，调节血管功能。我们在此报告一种三聚体ACE2变体的特性，该变体通过基于结构的方法构建，对新冠病毒刺突（S）蛋白的结合亲和力约为60 pM，同时保留野生型肽酶活性以及阻断RAS中1型血管紧张素II受体激活的能力。此外，工程化的ACE2在细胞培养中能有效抑制新冠病毒感染。这些结果表明，工程化的三聚体ACE2可能是一种有前景的抗新冠病毒药物，可用于治疗新冠。
