Protein scaffold-based multimerization of soluble ACE2 efficiently blocks SARS-CoV-2 infection in vitro and in vivo

Abstract

Soluble ACE2 (sACE2) decoy receptors are promising agents to inhibit SARS-CoV-2 as they are not affected by common escape mutations in viral proteins. However, their success may be limited by their relatively poor potency. To address these challenges, we developed a highly active multimeric sACE2 decoy receptor via a SunTag system that could neutralize both pseudoviruses bearing SARS-CoV-2 spike protein and SARS-CoV-2 clinical isolates. This fusion protein demonstrated a neutralization efficiency nearly 250-fold greater than monomeric sACE2. SunTag in combination with a more potent version of sACE2 achieved near complete neutralization at a sub-nanomolar range, which is comparable with clinical monoclonal antibodies. We demonstrate that this activity is due to greater occupancy of the multimeric decoy receptors on Spike protein as compared to monomeric sACE2. Overall, these highly potent multimeric sACE2 decoy receptors offer a promising treatment approach against SARS-CoV-2 infections including its novel variants.

Investigation of the Antiviral Effects of Saussurea lappa Root Extract against SARS‐CoV‐2 Virus

“…During the first 3 days of the experiment, 50 µL of 10 5 TCID 50 SARS‐CoV‐2 virus was intranasally administered under anesthesia, and S. lappa extract was administered as gavage in the afternoon. [ 37 ] Drugs were applied to the virus in the SARS‐CoV‐2 challenge experiment for 4 days in treatment trials. S. lappa was applied 4 days after the last virus application in the study.…”

Ultrapotent and Broad Neutralization of SARS-CoV-2 Variants by Modular, Tetravalent, Bi-paratopic Antibodies

“…Cocktails of two nAbs, ideally with non-overlapping epitopes, have been shown to be more potent and resistant to virus escape, but the considerable complexity and expense of combining two nAbs makes this approach problematic (Baum et al, 2020;Hansen et al, 2020;Weinreich et al, 2021). Alternatively, small modular Ab variable domains or non-antibody scaffolds have been assembled as multimers that can simultaneously engage all three RBDs on an S-protein trimer and thus enhance potency beyond bivalent binding (Cao et al, 2020;Hunt et al, 2021;Kayabolen et al, 2021;Walser et al, 2021;Xu et al, 2021). In another approach, a bispecific, bivalent IgG -with each arm targeting a different epitope on the RBD -has been shown to neutralize VoCs that escape from conventional IgGs (de Gasparo et al, 2020).…”