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bioRxiv · 10.1101/2020.08.31.274704

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

Guo, L.·Bi, W.·Wang, X.·Xu, W.·Yan, R.·Zhang, Y.·Zhao, K.·Li, Y.·Zhang, M.·Bao, X.·Cai, X.·Qu, D.·Jiang, S.·Xie, Y.·Zhou, Q.·Lu, L.·Dang, B.
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Abstract

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.

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Guo, L., Bi, W., Wang, X., Xu, W., Yan, R., Zhang, Y., Zhao, K., Li, Y., Zhang, M., Bao, X., Cai, X., Qu, D., Jiang, S., Xie, Y., Zhou, Q., Lu, L., Dang, B.. 2020-09-01. Engineered Trimeric ACE2 Binds and Locks "Three-up" Spike Protein to Potently Inhibit SARS-CoVs and Mutants. https://doi.org/10.1101/2020.08.31.274704

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