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Figure 1. Soluble ACE2 neutralizes SARS-CoV-2 infection.Soluble ACE2 (violet) competes with native, membrane-anchored ACE2
receptors (blue) for binding sites on viral spikes (green).
Figure 2. Selection strategies for enhancing the affinity of
ACE2 for the RBD of SARS-CoV-2. (A) In human cell selections of ACE2
variants, surface expression of full-length ACE2 with N-terminal epitope
tags was detected via fluorescent anti-tag antibodies. Cells expressing
ACE2 clones with high binding to RBD-sfGFP were collected by FACS.(B) In FACS selections of yeast, the protease domain of ACE2
was expressed as a fusion to Aga2p for display on the yeast surface.
Displayed protein was detected via a C-terminal fusion to GFP or
immunostaining of an epitope tag in the connecting linker. Bound RBD was
labeled via biotin or an epitope tag for fluorescence detection.(C) Structure (PDB 6M17) of RBD (green) bound to ACE2 (pale
blue). Common mutations in high affinity engineered decoys are indicated
in parentheses. (D) Mutational landscape showing how single
amino acid substitutions in ACE2 increase (blue) or decrease (red)
binding to RBD. Data are from Chan et al43.
Figure 3. Common modifications to soluble ACE2: fusions with
IgG-Fc and elimination of catalytic activity. (A) The Fc region of IgG
can be fused to the extracellular domains of ACE2. The Fc moiety is
recognized by inflammatory FcγRs on various cell types for immune
effector functions. IgG-Fc also binds FcRn within endosomal compartments
following pinocytosis by endothelial and epithelial cells to mediate
recycling or transcytosis, impacting biodistribution and serum
stability. (B) The conversion of angiotensin peptide hormones
by renin, ACE1 and ACE2.
Figure 4. Strategies to increase sACE2•S avidity. S of
SARS-CoV-2 binds the monomeric ACE2 protease domain (a.a. 19-615). A
longer version of sACE2 (a.a. 19-732/740) forms a stable dimer that
avidly binds virus. Higher levels of multimerization can be accomplished
by various N- or C-terminal fusions to IgG heavy and light chains.
Trimeric sACE2 proteins have also been constructed to complement
trimeric S spikes. Finally, ACE2 has been fused to an anti-SARS-CoV-2
monoclonal to create an avid biparatopic antibody hybrid.