Division of Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Nat Struct Mol Biol. 2021 Feb;28(2):202-209. doi: 10.1038/s41594-020-00549-3. Epub 2021 Jan 11.
Effective intervention strategies are urgently needed to control the COVID-19 pandemic. Human angiotensin-converting enzyme 2 (ACE2) is a membrane-bound carboxypeptidase that forms a dimer and serves as the cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 is also a key negative regulator of the renin-angiotensin system that modulates vascular functions. We report here the properties of a trimeric ACE2 ectodomain variant, engineered using a structure-based approach. The trimeric ACE2 variant has a binding affinity of ~60 pM for the spike protein of SARS‑CoV‑2 (compared with 77 nM for monomeric ACE2 and 12-22 nM for dimeric ACE2 constructs), and its peptidase activity and the ability to block activation of angiotensin II receptor type 1 in the renin-angiotensin system are preserved. Moreover, the engineered ACE2 potently inhibits SARS‑CoV‑2 infection in cell culture. These results suggest that engineered, trimeric ACE2 may be a promising anti-SARS-CoV-2 agent for treating COVID-19.
需要有效的干预策略来控制 COVID-19 大流行。人类血管紧张素转换酶 2（ACE2）是一种膜结合的羧肽酶，形成二聚体，是严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）的细胞受体。ACE2 也是肾素-血管紧张素系统的关键负调节剂，调节血管功能。我们在这里报告了一种基于结构的方法设计的三聚体 ACE2 外域变体的特性。三聚体 ACE2 变体与单体 ACE2 的 77 nM 和二聚体 ACE2 构建体的 12-22 nM 相比，对 SARS-CoV-2 刺突蛋白的结合亲和力约为 60 pM，其肽酶活性和阻断肾素-血管紧张素系统中血管紧张素 II 受体 1 激活的能力得以保留。此外，工程化的 ACE2 可有效抑制 SARS-CoV-2 在细胞培养物中的感染。这些结果表明，工程化的三聚体 ACE2 可能是治疗 COVID-19 的一种有前途的抗 SARS-CoV-2 药物。
