Trimerization of the N-terminal Domain of ACE2 for Bifunctional Trapping of Future SARS-CoV-2 Variants

NIH Pandemic-Era Grants

Pandemic Era Grants

2022

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Principal Investigator: Rihe  Liu
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2022
Award: $194,375
Funding agency: National Institute of Allergy and Infectious Diseases

Abstract
 The Covid-19 pandemic caused by SARS-Cov-2 has resulted in 38.3 million infection cases across 188
countries and territories with more than 1.08 million deaths by October 14 2020. While various vaccines are
under expedite development, there is a serious concern that future variants of SARS-COV-2 will evolve and
infect humans in the near future. We propose to develop a novel class of universal molecular blockers against
SARS-CoV-2 based on the N-terminal three-helix bundle (3HB, residues 20-99) of hACE2, which is recognized
by both SARS-CoV and SARS-CoV-2 as cell surface receptor to infect human cells. Based on our previous work
in trimerizing three-helical bundle domains, we hypothesize that the N-terminal 3HB domain of hACE2 can be
trimerized for highly potent and specific binding with presumably the RBD of all variants of SARS-CoV-2. Two
specific aims will be pursued in this project. In specific aim 1, we will develop a trimeric trap based on the N-
terminal three-helix bundle (3HB) of hACE2 that trivalently binds to the RBD of SARS-CoV-2 with high specificity
and potency. In specific aim 2, we will use directed molecular evolution to identify a human furin inhibitor from a
protein domain library and fuse it with the N-terminal 3HB of hACE2 for a bifunctional SARS-CoV-2 trap that
highly specifically binds viral RBD while inhibits its furin-mediated preactivation. The resulting novel SARS-CoV-
2 trapping molecules will have the potential to be universally applied to block hACE2-mediated infection by vast
majority of, if not all, future variants of SARS-CoV-2.

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