A trimeric human angiotensin-converting enzyme 2 as an anti-SARS-CoV-2 agent

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

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 SARS‑CoV‑2. ACE2 is also a key negative regulator of the renin-angiotensin system (RAS) 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 (S) protein of SARS‑CoV‑2 (compared to 77 nM for monomeric ACE2 and 12–22 nM for dimeric ACE2 constructs), while preserving its peptidase activity and 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.