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Engineered Trimeric ACE2 Binds and Locks “Three-up” Spike Protein to Potently Inhibit SARS-CoVs and Mutants

By Liang Guo, Wenwen Bi, Xinling Wang, Wei Xu, Renhong Yan, Yuanyuan Zhang, Kai Zhao, Yaning Li, Mingfeng Zhang, Xingyue Bao, Xia Cai, Yutang Li, Di Qu, Shibo Jiang, Youhua Xie, Qiang Zhou, Lu Lu, Bobo Dang

Posted 01 Sep 2020
bioRxiv DOI: 10.1101/2020.08.31.274704 (published DOI: 10.1038/s41422-020-00438-w)

SARS-CoV-2 enters cells via ACE-2, which binds the spike protein with moderate affinity. Despite a constant background mutational rate, the virus must retain binding with ACE2 for infectivity, providing a conserved constraint for SARS-CoV-2 inhibitors. To prevent mutational escape of SARS-CoV-2 and to prepare for future related coronavirus outbreaks, we engineered a de novo trimeric ACE2 (T-ACE2) protein scaffold that binds the trimeric spike protein with extremely high affinity (KD < 1 pM), while retaining ACE2 native sequence. T-ACE2 potently inhibits all tested pseudotyped viruses including SARS-CoV-2, SARS-CoV, eight naturally occurring SARS-CoV-2 mutants, two SARSr-CoVs as well as authentic SARS-CoV-2. The cryo-EM structure reveals that T-ACE2 can induce the transit of spike protein to “three-up” RBD conformation upon binding. T-ACE2 thus represents a promising class of broadly neutralizing proteins against SARS-CoVs and mutants. ### Competing Interest Statement BD, LG, WB are the inventors on a provisional patent filing by the Westlake University. The other authors declare no competing interests.

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